Chromane, isochromane and dihydroisobenzofuran derivatives as mGluR2—negative allosteric modulators, compositions, and their use

ABSTRACT

The present invention provides certain substituted chromane, isochromane, and dihydroisobenzofuran compounds of formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             or a pharmaceutically acceptable salt thereof, wherein ring A is a moiety selected from: 
           
         
       
    
                         
and ring B, n, R 1 , R 2 , R 2A , R 3 , and R 3A  are as defined herein. The compounds of the invention are useful as mGluR2 inhibitors, or mGluR2 negative allosteric modulators (NAMs), and may be useful in methods of treating a patient for diseases or disorders in which the mGluR2-NAM receptor is involved, such as Alzheimer&#39;s disease, cognitive impairment, mild cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, (optionally in combination with one or more additional active ingredients), and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

FIELD OF THE INVENTION

The invention is directed to certain chromane, isochromane, anddihydroisobenzofuran derivatives, their salts, pharmaceuticalcompositions comprising them and their use in therapy of the human body.The compounds of the invention have been found to modulate themetabotropic glutamate receptor 2 (mGluR2), and hence are expected to beuseful in the treatment of Alzheimer's Disease and other diseasesmediated by the mGluR2 receptor.

BACKGROUND OF THE INVENTION

The metabotropic glutamate receptors are known to contain one or moreallosteric sites, which may alter the affinity with which glutamate andother metabotropic glutamate (mGluR) ligands bind to the primary bindingor orthosteric sites. As the orthosteric binding site is highlyconserved between all of the known metabotropic glutamate receptors,functional selectivity may best be achieved through allostericinteraction with the receptor.

Modulation of metabotropic glutamate receptor 2 (mGluR2), which isprevalent on presynaptic nerve terminals in the cortex and hippocampusand regulates the release of the brain's major excitatoryneurotransmitter glutamate at key neural synapses, has been demonstratedto have a major role in cognitive processing. Neurodegenerative diseasesand disorders affecting cognition are thought to be influenced byglutamate signaling. Such neurodegenerative diseases and disordersaffecting cognition include (but are not limited to) various forms ofdementia, including dementia of the Alzheimer's type (Alzheimer'sdisease), including mild, moderate, and severe Alzheimer's disease, mildcognitive impairment, and others. Such diseases and disorders may resultin, or be identified by manifestations such as progressive memoryimpairment, loss of language and visuospatial skills, behavioraldeficits and others. The potential for inhibition of mGluR2 to improvecognitive performance has been demonstrated genetically andpharmacologically in preclinical species (Higgins et al. [2004],Neuropharmacology 46, 907-917). Further, inhibition of mGluR2/3 with anegative allosteric modulator shows precognitive effects in non-humanprimates (Goeldner et al., [2013], Neuropharmacology 64, 337-346).Similarly, mGluR2 inhibition with negative allosteric modulators isexpected to improve cognition and reverse dementia associated with otherdisorders, such as schizophrenia (Marek [2010], Eur J Pharmacol 639,81-90) and general mild cognitive impairment, since enhancement ofdownstream glutamatergic signaling has been shown to improve cognitionclinically (Lynch et al. [1997], Exp Neurol 145, 89-92). For thesereasons, inhibitors of mGluR2 are believed to be useful in improvementof cognitive performance associated with various forms of dementia,including Alzheimer's disease, cognitive impairment associated withschizophrenia, and other diseases and disorders. Patents have been fileddisclosing mGluR2/3 inhibitors for these (and other) indications(Celanire et al. [2015], Expert Opin Ther Patents 25, 69-90).

Given the capacity of presynaptic mGluR2 to modulate glutamate release,pharmacologic inhibition of mGluR2 with negative allosteric modulatorshas the capacity to enhance glutamate signaling to alleviate otherdisorders involving glutamate signaling. Among these are mood disordersincluding major depressive disorder (MDD), depression associated withbipolar disorder and anxiety. Inhibition of mGluR2 and mGluR3 byorthosteric antagonists have demonstrated efficacy in rodent models ofdepression (Chaki et al. [2004], Neuropharmacology 46, 457-67) as havenegative allosteric modulators (Campo et al. [2011], J Neurogenet 25,152-66). Antagonists of mGluR2 and mGluR3 have also demonstratedefficacy in rodent models of anxiety (Shimazaki et al. [2004], Eur JPharmacol 501, 121-5; Iijima et al. [2007], Psychopharmacology (Berl)190, 233-9) which has resulted in the filing of patents for mGluR2/3inhibitors for these (and other) indications (Celanire et al. [2015],Expert Opin Ther Patents 25, 69-90).

Inhibition of mGluR2 receptors with negative allosteric modulators isalso expected to modulate sleep and arousal and circadian timing ofsleep wake cycles. Activation of mGluR2 with a positive allostericmodulator results in deep sleep in rats and clinically in healthy humanvolunteers (Ahnaou et al. [2016], Neuropharmacology 103, 290-305) suchthat inhibition with a negative allosteric modulator is expected topromote arousal coincident with improved cognition. Glutamate signalingmodulated by group II mGluRs (mGluR2, mGluR3) is also involved in thecircadian timing of sleep/wake cycles such that inhibition of mGluR2 maybe expected to improve coordination of activity to environmentallight/dark cycles. Genetic loss of mGluR2 and mGluR3 as well aspharmacological inhibition with negative allosteric modulators to thesereceptors results in enhanced responses to light entrainment cues(Pritchett et al. [2015], PLoS One 10, e0125523).

Inhibition of mGluR2 with negative allosteric modulator compounds isalso expected to modulate pain sensation and responses to pain.Glutamate signaling mediates both the transmission of pain informationas well as peripheral and central mechanisms of pain hypersensitivitysuch that modulation of this signaling via mGluR2 inhibition has thepotential to impact nociception as well as the central perception ofpain memory (Chiechio [2016], Adv Pharmacol 75, 63-89).

Certain substituted quinoline carboxamides, quinoline carbonitriles,tetrahydronaphthyridines, and others, are known in the art as mGluR2inhibitors or for other uses. See, for example, WO2016/032921,WO2013/066736, US Patent Application No. 2008/0188521, WO2007/038865, WO1996/13500, each disclosing compounds as leukotriene inhibitors, andCanadian Patent Application No. 2169231, disclosing compounds asleukotriene and SRS-A inhibitors. There remains a need in the art fornovel compounds that are effective as non-competitive mGluR2 modulators,and/or mGluR2 negative allosteric modulators (NAMs).

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed to certain novelsubstituted chromane, isochromane, and dihydroisobenzofuran derivatives,which are collectively or individually referred to herein as“compound(s) of the invention.” The compounds of the invention,described below, are non-competitive negative allosteric modulators ofthe metabotropic glutamate 2 receptor (mGluR2 NAMs), and may be usefulin treating diseases or disorders in which inhibition of the mGluR2receptor is useful. Such diseases or disorders include, but may not belimited to, Alzheimer's disease, cognitive impairment, schizophrenia andother mood disorders, pain disorders, and sleep disorders. In anotherembodiment, the present invention is also directed to pharmaceuticalcompositions comprising an effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, and, in yet another embodiment, tothe use of the compounds and pharmaceutical compositions of theinvention in the treatment of such diseases or disorders. In otherembodiments, the present invention is also directed to a combinationcomprising a compound of the invention and one, two, three or more othertherapeutic agents, and for the use of said combination in the treatmentof the diseases or disorders described herein. These and otherembodiments are described in detail hereinbelow.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the compounds of the invention have the structuralFormula (I):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, wherein:

ring A is a moiety selected from:

wherein:

R² is selected from H, cyclopropyl, —(C₁-C₄)alkyl, —(C₁-C₄)alkyl-OH,—(C₁-C₄)alkyl-OCH₃, —(C₁-C₄)haloalkyl, —(C₁-C₄)alkyl-O—(C₁-C₄)haloalkyl,—CH₂—O—(C₁-C₄)haloalkyl, —CH(CH₃)—O—(C₁-C₄)haloalkyl,—CH₂—NH—(C₁-C₄)haloalkyl, and —CH₂—N(CH₃)—(C₁-C₄)haloalkyl,

R^(2A) is selected from H and methyl;

R³ is selected from H and methyl;

R^(3A) is selected from H and methyl;

ring B is a moiety selected from the group consisting of phenyl,heteroaryl, —(C₅-C₆) cycloalkyl, and —(C₅-C₆) cycloalkenyl;

n is 0, 1, 2, or 3, provided that the value of n does not exceed themaximum number of substitutable hydrogen atoms on ring B; and

each R¹ (when present) is independently selected from the groupconsisting of halogen, —CN, —OH, —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl,—(C₁-C₆) haloalkyl, —O—(C₁-C₆) haloalkyl, cyclopropyl, cyclobutyl, —NH₂,—NH(C₁-C₆)alkyl, —N(C₁-C₆alkyl)₂, —C(O)O(C₁-C₆) alkyl, and phenyl.

In embodiments wherein ring A is the moiety:

Formula (I) takes the form of Formula (IA):

wherein ring B, n, and each R¹ are as defined in Formula (I).

In one embodiment, in Formula (IA):

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R^(2A) is selected from H and methyl;

R³ is selected from H and methyl;

R^(3A) is selected from H and methyl;

and ring B, n, and each R¹ is as defined in Formula I.

In another embodiment, in Formula (IA):

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R^(2A) is selected from H and methyl;

R³ is selected from H and methyl;

R^(3A) is H;

and ring B, n, and each R¹ is as defined in Formula I.

In another embodiment, in Formula (IA):

R² and R^(2A) are both methyl;

R³ and R^(3A) are both H;

and ring B, n, and each R¹ is as defined in Formula I.

In another alternative of the immediately preceding embodiment,

In embodiments wherein ring A is the moiety:

Formula (I) takes the form of Formula (IB):

wherein ring B, n and each R¹ are as defined in Formula (I).

In embodiments wherein ring A is the moiety:

Formula (I) takes the form of Formula (IC):

wherein ring B, n and each R¹ are as defined in Formula (I).

In embodiments wherein ring A is the moiety:

Formula (I) takes the form of Formula (ID):

wherein ring B, n and each R¹ are as defined in Formula (I).

The following alternative embodiments of ring B, n, and R¹ apply to eachof the embodiments described above.

In one embodiment, in each of Formulas (I), (IA), (IB), (IC), and (ID):

ring B is a moiety selected from the group consisting of phenyl,cyclopentyl, cyclohexyl, pyridinyl, pyrimidinyl, pyrazolyl, thienyl,thiazolyl, thiadiazolyl, isoxazolyl, oxadiazolyl and oxazolyl;

n is 0, 1, 2, or 3, provided that the value of n does not exceed themaximum number of substitutable hydrogen atoms on ring B; and

each R¹ (when present) is independently selected from the groupconsisting of halogen, —CN, —OH, —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl,—(C₁-C₆) haloalkyl, —O—(C₁-C₆) haloalkyl, cyclopropyl, cyclobutyl, —NH₂,—NH(C₁-C₆)alkyl, —N(C₁-C₆alkyl)₂, —C(O)O(C₁-C₆) alkyl, and phenyl.

In an alternative of the immediately preceding embodiment, n is 0, 1, or2; and

each R¹ (when present) is independently selected from the groupconsisting of fluoro, chloro, —CN, —OH, —(C₁-C₆) alkyl, —O—(C₁-C₆)alkyl, —(C₁-C₆) haloalkyl, —O—(C₁-C₆) haloalkyl, cyclopropyl,cyclobutyl, —NH₂, —NH(C₁-C₆)alkyl, —N(C₁-C₆alkyl)₂, —C(O)O(C₁-C₆) alkyl,and phenyl.

In another embodiment, in each of Formulas (I), (IA), (IB), (IC), and(ID):

ring B is a moiety selected from the group consisting of: phenyl,pyrazolyl, pyridinyl, thienyl, isoxazolyl, oxadiazolyl and oxazolyl;

n is 0, 1, 2, or 3; and

each R¹ (when present) is independently selected from the groupconsisting of fluoro, chloro, —CN, —OH, —(C₁-C₆) alkyl, —O—(C₁-C₆)alkyl, —(C₁-C₆) haloalkyl, —O—(C₁-C₆) haloalkyl, cyclopropyl,cyclobutyl, —NH₂, —NH(C₁-C₆)alkyl, —N(C₁-C₆alkyl)₂, —C(O)O(C₁-C₆) alkyl,and phenyl.

In an alternative of the immediately preceding embodiment, n is 0, 1, or2.

In another embodiment, in each of Formulas (I), (IA), (IB), (IC), and(ID):

ring B is a moiety selected from the group consisting of: phenyl,pyrazolyl, pyridinyl, thienyl, isoxazolyl, oxadiazolyl and oxazolyl;

n is 0, 1, 2, or 3; and

each R¹ (when present) is independently selected from the groupconsisting of fluoro, chloro, —CH₃, and —CHCF₂.

In an alternative of the immediately preceding embodiment, n is 0, 1, or2.

Non-limiting examples of ring B, n, and R¹ are shown in thecorresponding position of each of the example compounds of the inventionas shown in the preparative examples and appended claims.

As described in Formulas (I), (IA), (IB), (IC), and (ID), and in each ofthe alternative embodiments of ring B, n and R¹ recited herein, ring Bcan be substituted with 0, 1, 2, or 3 independently selected R¹ groups,provided that the value of n does not exceed the maximum number ofsubstitutable hydrogen atoms on ring B. Thus, in embodiments whereinring B is phenyl, —(C₅-C₆) cycloalkyl, —(C₅-C₆) cycloalkenyl, pyridinyl,pyrimidinyl, or thienyl, n is 0, 1, 2, or 3. In an alternative of eachsuch embodiment, n is 0, 1, or 2. In another alternative of each suchembodiment, n is 0 or 1. When ring B is pyrazolyl, thiazolyl,isoxazolyl, oxadiazolyl, or oxazolyl, n is 0, 1, or 2. In an alternativeof each such embodiment, n is 0 or 1. And when ring B is thiadiazolyl, nis 0 or 1.

Another embodiment is a compound of Formula (IA-1):

or a stereoisomer thereof or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, wherein:

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R^(2A) is selected from H and CH₃;

R³ is selected from H and CH₃; and

R^(3A) is selected from H and CH₃.

Another embodiment is a compound of Formula (IA-1), or a stereoisomerthereof, or a pharmaceutically acceptable salt of said compound or saidstereoisomer, wherein:

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R^(2A) is selected from H and CH₃;

R³ is selected from H and CH₃; and

R^(3A) is H.

Another embodiment is a compound of Formula (IA-1), or a stereoisomerthereof, or a pharmaceutically acceptable salt of said compound or saidstereoisomer, wherein:

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R^(2A) is H;

R³ is selected from H and CH₃; and

R^(3A) is H.

Another embodiment is a compound of Formula (IA-1), or a stereoisomerthereof, or a pharmaceutically acceptable salt of said compound or saidstereoisomer, wherein:

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R^(2A) is H;

R³ is H; and

R^(3A) is H.

Another embodiment is a compound of Formula (IA-1a):

or a pharmaceutically acceptable salt thereof, wherein:

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R³ is H; and

R^(3A) is CH₃.

Another embodiment is a compound of Formula (IA-1a), or a stereoisomerthereof, or a pharmaceutically acceptable salt of said compound or saidstereoisomer, wherein:

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R³ is CH₃; and

R^(3A) is H.

Another embodiment is a compound of Formula (IA-1a), or a stereoisomerthereof, or a pharmaceutically acceptable salt of said compound or saidstereoisomer, wherein:

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R³ is H; and

R^(3A) is H.

Another embodiment is a compound of Formula (IA-1b):

or a pharmaceutically acceptable salt thereof, wherein:

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R³ is H; and

R^(3A) is CH₃.

Another embodiment is a compound of Formula (IA-1b), or a stereoisomerthereof, or a pharmaceutically acceptable salt of said compound or saidstereoisomer, wherein:

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R³ is CH₃; and

R^(3A) is H.

Another embodiment is a compound of Formula (IA-1b), or a stereoisomerthereof, or a pharmaceutically acceptable salt of said compound or saidstereoisomer, wherein:

R² is selected from H, cyclopropyl, —CH₃, —CH(CH₃)₂, —CH₂—OH, —CH₂—OCH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂—O—CH₂F,—CH₂—O—CHF₂, —CH(CH₃)—O—CH₂F, —CH(CH₃)—O—CHF₂, —CH₂—NH—CH₂CF₃, and—CH₂—N(CH₃)—CH₂CF₃;

R³ is H; and

R^(3A) is H.

In one embodiment, the compounds of the invention comprise, collectivelyand individually, each of the example compounds shown in the tablesbelow, and pharmaceutically acceptable salts thereof. Suitablepharmaceutically acceptable salts of each of these compounds includethose discussed hereinbelow.

Definitions

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names and chemical structures may be used interchangeablyto describe that same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence the definition of“alkyl” applies to“alkyl” as well as the “alkyl” portion of “hydroxyalkyl”, “haloalkyl”,arylalkyl-, alkylaryl-, “alkoxy” etc.

It shall be understood that, in the various embodiments of the inventiondescribed herein, any variable not explicitly defined in the context ofthe embodiment is as defined in Formula (I). All valences not explicitlyfilled are assumed to be filled by hydrogen.

“Patient” means a human in need of a treatment described herein, asdetermined by an attending physician or other health care professionalor by any other suitable method known to those of skill in the art.While the subject or patient to whom the compounds and compositions ofthe present invention are administered is generally a human being, suchsubjects may also include non-human mammals, including dogs, cats, mice,rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apesor primates, for which treatment the above noted diseases and disorders,or the study of the biological activity of the subject compounds, isdesired.

“Pharmaceutical composition” (or “pharmaceutically acceptablecomposition”) means a composition suitable for administration to apatient. Such compositions may contain the compound (or compounds) ofthe invention or mixtures thereof, or salts, solvates, prodrugs,isomers, or tautomers thereof, alone or optionally together with one ormore pharmaceutically acceptable carriers or diluents. The term“pharmaceutical composition” is also intended to encompass both the bulkcomposition and individual dosage units comprised of more than one(e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

“Halogen” (or “halo”) means fluorine (F), chlorine (Cl), bromine (Br),or iodine (I). Preferred are fluorine, chlorine and bromine. Morepreferred are fluorine and chlorine.

“Alkyl” means an aliphatic hydrocarbon group, which may be straight orbranched, comprising 1 to 6 carbon atoms. “Lower alkyl” means a straightor branched alkyl group comprising 1 to 4 carbon atoms. Branched meansthat one or more lower alkyl groups such as methyl, ethyl or propyl, areattached to a linear alkyl chain. Non-limiting examples of suitablealkyl groups include methyl (Me or CH₃), ethyl (Et), n-propyl,isopropyl, n-butyl, i-butyl, and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising 2 to 10 carbon atoms in the straight or branched chain.Branched means that one or more lower alkyl groups such as methyl, ethylpropyl, ethenyl or propenyl are attached to a linear or branched_alkenylchain. “Lower alkenyl” means 2 to 4 carbon atoms in the chain which maybe straight or branched. Non-limiting examples of suitable alkenylgroups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl,n-pentenyl, octenyl and decenyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in whichone or more of the ring atoms is an element other than carbon, forexample nitrogen, oxygen or sulfur, alone or in combination. Preferredheteroaryls contain 5 to 6 ring atoms. The “heteroaryl” can beoptionally substituted by one or more substituents, which may be thesame or different, as defined herein. The prefix aza, oxa or thia beforethe heteroaryl root name means that at least a nitrogen, oxygen orsulfur atom respectively, is present as a ring atom. A nitrogen atom ofa heteroaryl can be optionally oxidized to the corresponding N-oxidewithout falling outside of the definition of heteroaryl. “Heteroaryl”may also include a heteroaryl as defined above fused to an aryl asdefined above. Non-limiting examples of suitable heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl (which alternatively may bereferred to as thiophenyl), pyrimidinyl, pyridone (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl,triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl,imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl,quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl,isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and thelike. The term “heteroaryl” also refers to partially saturatedheteroaryl moieties such as, for example, tetrahydroisoquinolyl,tetrahydroquinolyl and the like. The term “monocyclic heteroaryl” refersto monocyclic versions of heteroaryl as described above and includes 4-to 7-membered monocyclic heteroaryl groups comprising from 1 to 4 ringheteroatoms, said ring heteroatoms being independently selected from N,O, and S, and oxides thereof. The point of attachment to the parentmoiety is to any available ring carbon or ring heteroatom. Non-limitingexamples of monocyclic heteroaryl moities include pyridyl (orpyridinyl), pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl,pyridoneyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl,pyrazolyl, furazanyl, pyrrolyl, triazolyl, thiadiazolyl (e.g.,1,2,4-thiadiazolyl), imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl),and oxides thereof.

“Cycloalkyl” means a non-aromatic monocyclic or multicyclic ring systemcomprising 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms. Thecycloalkyl can be optionally substituted with one or more substituents,which may be the same or different, as described herein. Monocycliccycloalkyl refers to monocyclic versions of the cycloalkyl moietiesdescribed herein. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of multicyclic cycloalkyls include[1.1.1]-bicyclopentane, 1-decalinyl, norbornyl, adamantyl and the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising 3 to 10 carbon atoms, preferably 4 to 6 carbon atoms whichcontain at least one carbon-carbon double bond. Preferred cycloalkenylrings contain 5 to 6 ring atoms. The term “monocyclic cycloalkenyl”refers to monocyclic versions of cycloalkenyl groups described hereinand includes non-aromatic 3- to 7-membered monocyclic cycloalkyl groupswhich contains one or more carbon-carbon double bonds. Non-limitingexamples include cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cyclohetpenyl, cyclohepta-1,3-dienyl, and the like.Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

Any of the foregoing functional groups may be unsubstituted orsubstituted as described herein. The term “substituted” means that oneor more hydrogens on the designated atom is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalency under the existing circumstances is not exceeded, and that thesubstitution results in a stable compound. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds. By “stable compound” or “stable structure” is meant acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

When a variable appears more than once in a group, e.g., R⁶ in —N(R⁶)₂,or a variable appears more than once in a structure presented herein,the variables can be the same or different.

The line —, as a bond generally indicates a mixture of, or either of,the possible isomers, e.g., containing (R)- and (S)-stereochemistry. Forexample:

means containing both

and/or

The wavy line

, as used herein, indicates a point of attachment to the rest of thecompound. Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

“Oxo” means an oxygen atom that is double bonded to a ring carbon in acycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or such otherrings as are described herein, e.g.,

In this specification, where there are multiple oxygen and/or sulfuratoms in a ring system, there cannot be any adjacent oxygen and/orsulfur present in said ring system.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

represents

In another embodiment, the compounds of the invention, and/orcompositions comprising them, are present in isolated and/or purifiedform. The term “purified”, “in purified form” or “in isolated andpurified form” for a compound refers to the physical state of saidcompound after being isolated from a synthetic process (e.g. from areaction mixture), or natural source or combination thereof. Thus, theterm “purified”, “in purified form” or “in isolated and purified form”for a compound refers to the physical state of said compound (or atautomer thereof, or pharmaceutically acceptable salt of said compoundor said tautomer) after being obtained from a purification process orprocesses described herein or well known to the skilled artisan (e.g.,chromatography, recrystallization and the like), in sufficient purity tobe suitable for in vivo or medicinal use and/or characterizable bystandard analytical techniques described herein or well known to theskilled artisan.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

Those skilled in the art will recognize those instances in which thecompounds of the invention may be converted to prodrugs and/or solvates,another embodiment of the present invention. A discussion of prodrugs isprovided in T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems (1987) 14 of the A.C.S. Symposium Series, and in BioreversibleCarriers in Drug Design, (1987) Edward B. Roche, ed., AmericanPharmaceutical Association and Pergamon Press. The term “prodrug” meansa compound (e.g, a drug precursor) that is transformed in vivo to yielda compound of the invention or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvarious mechanisms (e.g., by metabolic or chemical processes), such as,for example, through hydrolysis in blood. A discussion of the use ofprodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as NovelDelivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms where they exist. “Solvate”means a physical association of a compound of the invention with one ormore solvent molecules. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” means an amountof compound or a composition of the present invention that will elicitthe biological or medical response of a tissue, system, animal or humanthat is being sought by the researcher, vererinarian, medical doctor orother clinician or practitioner. In the combination therapies of thepresent invention, an effective amount can refer to each individualagent or to the combination as a whole, wherein the amounts of allagents administered are together effective. In some embodiments, one ormore component agents of the combination may be present individually inan amount less than the amount needed to be effective when administeredalone, as described further below. A “therapeutically effective amount”can vary depending on, inter alia, the compound, the disease and itsseverity, and the age, weight, etc., of the subject to be treated.

The term “treatment” or “treating” means any administration of acompound or composition of the present invention to a subject in needthereof, alone or in combination with one or more additional therapeuticagents, and includes (1) inhibiting or ameliorating a pathology and/orsymptamotology of the disease or disorder in said subject, e.g., animal,person or patient or other subject that is experiencing or displayingthe pathology or symptomatology of the disease or disorder. The term“prevention” or “prophylaxis,” means any administration of a compound orcomposition of the present invention to a subject in need thereof, aloneor in combination with one or more additional therapeutic agents, andincludes (1) inhibiting or ameliorating a pathology and/orsymptamotology of the disease or disorder in said subject, e.g., animal,person or patient or other subject prior to the onset or manifestationof the pathology or symptomatology of the disease or disorder. The term“controlling” includes preventing, treating, eradicating, amelioratingor otherwise reducing the severity of the disease or disorder or symptomor symptoms thereof.

The compounds and compositions of the present invention, alone or incombination with one or more additional therapeutic agents, may also beuseful in the treatment or prevention of the diseases or disordersmentioned, or one or more symptoms thereof, which treatments andprevention are also contemplated as additional embodiments of thepresent invention.

Those skilled in the art will recognize those instances in which thecompounds of the invention may form salts. In such instances, anotherembodiment provides pharmaceutically acceptable salts of the compoundsof the invention. The term “salt(s)”, as employed herein, denotes any ofthe following: acidic salts formed with inorganic and/or organic acids,as well as basic salts formed with inorganic and/or organic bases. Inaddition, when a compound of the invention contains both a basic moiety,such as, but not limited to a pyridine or imidazole, and an acidicmoiety, such as, but not limited to a carboxylic acid, zwitterions(“inner salts”) may be formed and are included within the term “salt(s)”as used herein. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, although other saltsare also potentially useful. Salts of the compounds of the invention maybe formed by methods known to those of ordinary skill in the art, forexample, by reacting a compound of the invention with an amount of acidor base, such as an equivalent amount, in a medium such as one in whichthe salt precipitates or in an aqueous medium followed bylyophilization.

Exemplary acid addition salts which may be useful include acetates,ascorbates, benzoates, benzenesulfonates, bisulfates, borates,butyrates, citrates, camphorates, camphorsulfonates, fumarates,hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,methanesulfonates, naphthalenesulfonates, nitrates, oxalates,phosphates, propionates, salicylates, succinates, sulfates, tartarates,thiocyanates, toluenesulfonates (also known as tosylates) and the like.Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered as potentially useful alternatives to the freeforms of the corresponding compounds for purposes of the invention.

Another embodiment which may be useful includes pharmaceuticallyacceptable esters of the compounds of the invention. Such esters mayinclude the following groups: (1) carboxylic acid esters obtained byesterification of the hydroxy groups, in which the non-carbonyl moietyof the carboxylic acid portion of the ester grouping is selected fromstraight or branched chain alkyl (for example, acetyl, n-propyl,t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl(for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl(for example, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di(C₆₋₂₄)acyl glycerol.

The compounds of the invention may have one or more chiral (asymmetric)centers. The present invention encompasses all stereoisomeric forms ofthe compounds of formula I. Centers of asymmetry that are present in thecompounds of Formula I can all independently of one another have an (R)or (S) configuration. As noted above, when bonds to a chiral carbon aredepicted as straight lines in the structural Formulas of the invention,or when a compound name is recited without an (R) or (S) chiraldesignation for a chiral carbon, it is understood that both the (R) and(S) configurations of each such chiral carbon, and hence each enantiomeror diastereomer and mixtures thereof, are embraced within the Formula orby the name.

Where various stereoisomers of the compounds of the invention arepossible, another embodiment provides for diastereomeric mixtures andindividual enantiomers of the compounds of the invention. Diastereomericmixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods well known tothose skilled in the art, such as, for example, by chromatography and/orfractional crystallization. Enantiomers can be separated by convertingthe enantiomeric mixture into a diastereomeric mixture by reaction withan appropriate optically active compound (e.g., chiral auxiliary such asa chiral alcohol or Mosher's acid chloride), separating thediastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers. Enantiomers canalso be separated by use of chiral HPLC column.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the compounds of the invention (including those of thesalts, solvates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs), such as those which mayexist due to asymmetric carbons on various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons), rotameric forms, atropisomers, and diastereomeric forms, arecontemplated as embodiments within the scope of this invention. (Forexample, if a compound of the invention incorporates a double bond or afused ring, both the cis- and trans-forms, as well as mixtures, areembraced within the scope of the invention. Also, for example, allketo-enol and imine-enamine forms of the compounds are included in theinvention.).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugsof the inventive compounds.

Another embodiment which may be useful include isotopically-labelledcompounds of the invention. Such compounds are identical to thoserecited herein, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number usually found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and³⁶Cl, respectively.

In the compounds of the invention, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of the invention. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundsof the invention can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the schemes and examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

Polymorphic forms of the compounds of the invention, and of the salts,solvates, esters and prodrugs of the compounds of the invention, areintended to be included in the present invention.

Compositions and Administration

Another embodiment provides pharmaceutical compositions which comprise atherapeutically effective amount of a compound of the invention, or astereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, and a pharmaceutically acceptablecarrier.

A representative dosage is about 0.001 to 100 mg/kg of body weight/dayof the compound of the invention. A preferred dosage is about 0.01 to 10mg/kg of body weight/day of a compound of the invention, or apharmaceutically acceptable salt of said compound.

The term “pharmaceutical composition” is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional therapeutic agentselected from the lists of the additional agents described herein below,along with any pharmaceutically inactive excipients. The bulkcomposition and each individual dosage unit can contain fixed amounts ofthe aforesaid “more than one pharmaceutically active agents”. The bulkcomposition is material that has not yet been formed into individualdosage units. An illustrative dosage unit is an oral dosage unit such astablets, pills and the like. Similarly, the herein-described method oftreating a patient by administering a pharmaceutical composition of thepresent invention is also intended to encompass the administration ofthe afore-said bulk composition and individual dosage units.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include, for example, solutions, suspensionsand emulsions. Examples of materials useful for forming such liquid formpreparations include water or water-propylene glycol solutions forparenteral injection, or sweeteners and opacifiers for oral solutions,suspensions and emulsions. Liquid form preparations may also includesolutions or suspensions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g., nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention can also be deliverable transdermally.The transdermal compositions can take the form of liquid solutions,creams, lotions, aerosols and/or emulsions and can be included in atransdermal patch of the matrix or reservoir type as are conventional inthe art for this purpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.001 mg to about 100 mg per kg bodyweight of a mammal, preferably from about 0.01 mg to about 10 mg per kg.The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The compositions of the invention can further comprise one or moreadditional therapeutic agents, as discussed in further detail below.Accordingly, in one embodiment, the present invention providescompositions comprising: (i) a compound of the invention, or astereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer; (ii) one or more additional therapeuticagents, that are not compounds of the invention; and (iii) apharmaceutically acceptable carrier, wherein the amounts in thecomposition are together effective to treat one of the disease orconditions discussed herein.

Uses of the Compounds of the Invention

Another embodiment provides a method of treating a patient (e.g., ahuman patient or a research animal) for diseases or disorders in whichthe mGluR2 receptor is involved. These methods comprise administering aneffective amount of a compound of the invention, or compositioncomprising a compound of the invention (or a stereoisomer thereof, or apharmaceutically acceptable salt of said compound or said stereoisomer),to a patient in need thereof, to treat a disease or disorder in whichthe mGluR2 receptor is involved.

Another embodiment provides for the use of a compound of the inventionfor treating a disease or disorder in which the mGluR2 receptor isinvolved, by administering an effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, to a patientin need thereof. Another embodiment provides for the use of a compoundof the invention for the manufacture of a medicament treating a diseaseor disorder in which the mGluR2 receptor is involved, by administeringan effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof, to a patient in need thereof.Examples of such diseases and disorders are described herein.

In one embodiment, the compounds of the invention useful in said methodsor said uses comprise a compound according to any one of Formulas (I),(IA), (IA-1), (IA-1a), (IA-1b), (IB), (IC), and (ID) as described above,or according to any of the various embodiments described herein, or astereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, or a pharmaceutically acceptablecomposition thereof. In another embodiment, the compounds of theinvention useful in said methods or said uses comprise the compound ofexample 2-5, or a pharmaceutically acceptable salt of said compound, ora pharmaceutically acceptable composition thereof. In anotherembodiment, the compound of the invention useful in said methods or saiduses comprises the compound of example 2-3A or a pharmaceuticallyacceptable salt of said compound, or a pharmaceutically acceptablecomposition thereof. In another embodiment, the compound of theinvention useful in said methods or said uses comprises the compound ofexample 2-3B or a pharmaceutically acceptable salt of said compound, ora pharmaceutically acceptable composition thereof. In anotherembodiment, the compound of the invention useful in said methods or saiduses comprises the compound of example 3-1A or a pharmaceuticallyacceptable salt of said compound, or a pharmaceutically acceptablecomposition thereof. In another embodiment, the compound of theinvention useful in said methods or said uses comprises the compound ofexample 3-1B or a pharmaceutically acceptable salt of said compound, ora pharmaceutically acceptable composition thereof. In anotherembodiment, the compound of the invention useful in said methods or saiduses comprises the compound of example 3-7A or a pharmaceuticallyacceptable salt of said compound, or a pharmaceutically acceptablecomposition thereof. In another embodiment, the compound of theinvention useful in said methods or said uses comprises the compound ofexample 3-7B or a pharmaceutically acceptable salt of said compound, ora pharmaceutically acceptable composition thereof.

In one embodiment, the present invention is directed to a method oftreating a neurodegenerative disease or disorders affecting cognition,said method comprising administering a compound of the invention, or astereoisomer thereof, or a pharmaceutically acceptable salt thereof, toa subject in need thereof. Such diseases or disorders affectingcognition include, but are not limited to, Alzheimer's disease,cognitive impairment, cognition associated with Parkinson's disease,schizophrenia, mood disorders, including depression and anxiety,gastrointestinal disorders, pain disorders and sleep disorders, andothers as described herein.

Additional examples of pain disorders include acute pain, inflammatorypain and neuropathic pain. Neuropathic pain includes, but is not limitedto, postherpetic neuralgia, nerve injury, the “dynias”, e.g.,vulvodynia, phantom limb pain, root avulsions, painful diabeticneuropathy, painful traumatic mononeuropathy, painful polyneuropathy.Additional examples of pain disorders include central pain syndromes(potentially caused by virtually any lesion at any level of the nervoussystem); postsurgical pain syndromes (eg, postmastectomy syndrome,postthoracotomy syndrome, stump pain); bone and joint pain(osteoarthritis), repetitive motion pain, dental pain, cancer pain,myofascial pain (muscular injury, fibromyalgia); perioperative pain(general surgery, gynecological), chronic pain, dysmennorhea, as well aspain associated with angina, and inflammatory pain of varied origins(e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease,teno-synovitis and gout), headache, migraine and cluster headache,headache, primary hyperalgesia, secondary hyperalgesia, primaryallodynia, secondary allodynia, or other pain caused by centralsensitization.

Additional examples of cognitive disorders include mild cognitiveimpairment. Other conditions that may be treated by the compounds andcompositions of the invention include Parkinson's Disease, pulmonaryhypertension, chronic obstructive pulmonary disease (COPD), asthma,urinary incontinence, glaucoma, Trisomy 21 (Down Syndrome), cerebralamyloid angiopathy, degenerative dementia, Hereditary CerebralHemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D),Creutzfeld-Jakob disease, prion disorders, amyotrophic lateralsclerosis, progressive supranuclear palsy, head trauma, stroke,pancreatitis, inclusion body myositis, other peripheral amyloidoses,diabetes, autism and atherosclerosis.

In preferred embodiments, the compounds of the invention may be usefulin treating Alzheimer's Disease, cognitive disorders, schizophrenia,pain disorders and sleep disorders. For example, the compounds may beuseful for the prevention of dementia of the Alzheimer's type, as wellas for the treatment of early stage, intermediate stage or late stagedementia of the Alzheimer's type.

Potential schizophrenia conditions or disorders for which the compoundsof the invention may be useful include one or more of the followingconditions or diseases: schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (phencyclidine, ketanine and other dissociativeanaesthetics, amphetamine and other psychostimulants and cocaine)psychosispsychotic disorder, psychosis associated with affectivedisorders, brief reactive psychosis, schizoaffective psychosis,“schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, or illness associated with psychosis (such asmajor depression, manic depressive (bipolar) disorder, Alzheimer'sdisease and post-traumatic stress syndrome), including both the positiveand the negative symptoms of schizophrenia and other psychoses;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, multi-infarct dementia, trauma, vascular problems orstroke, HIV disease, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeldt-Jacob disease, perinatal hypoxia, other generalmedical conditions or substance abuse); delirium, amnestic disorders orage related cognitive decline.

In another embodiment, the present invention provides a method fortreating schizophrenia or psychosis comprising administering to apatient in need thereof an effective amount of a compound (orcomposition providing a compound) of the invention, or a stereoisomerthereof.

Potential sleep conditions or disorders for which the compounds of theinvention may be useful include enhancing sleep quality; improving sleepquality; augmenting sleep maintenance; increasing the value which iscalculated from the time that a subject sleeps divided by the time thata subject is attempting to sleep; decreasing sleep latency or onset (thetime it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; increasing daytime alertness;reducing daytime drowsiness; treating or reducing excessive daytimesleepiness; insomnia; hypersomnia; narcolepsy; interrupted sleep; sleepapnea; wakefulness; nocturnal myoclonus; REM sleep interruptions;jet-lag; shift workers' sleep disturbances; dyssomnias; night terror;insomnias associated with depression, emotional/mood disorders, as wellas sleep walking and enuresis, and sleep disorders which accompanyaging; Alzheimer's sundowning; conditions associated with circadianrhythmicity as well as mental and physical disorders associated withtravel across time zones and with rotating shift-work schedules;conditions due to drugs which cause reductions in REM sleep as a sideeffect; syndromes which are manifested by non-restorative sleep andmuscle pain or sleep apnea which is associated with respiratorydisturbances during sleep; and conditions which result from a diminishedquality of sleep.

Compounds of the invention may also be used to treat or preventdyskinesias. Furthermore, compounds of the invention may be used todecrease tolerance and/or dependence to opioid treatment of pain, andfor treatment of withdrawal syndrome of e.g., alcohol, opioids, andcocaine.

The subject or patient to whom the compounds of the present invention isadministered is generally a human being, male or female, in whom mGluR2receptor inhibition is desired, but may also encompass other mammalssuch as those listed above, including dogs, cats, mice, rats, cattle,horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates,for which treatment the above noted disorders, or the study of mGluR2,is desired.

Another embodiment provides a medicament or pharmaceutical compositionfor the negative allosteric modulation of an mGluR2 receptor, and/or forthe treatment of any of the diseases or disorders listed above to apatient (preferably a human) in need of such treatment, which comprise acompound (or composition comprising a compound) of the invention, or astereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, and a pharmaceutically acceptablecarrier.

Another embodiment provides a method for the manufacture of a medicamentor a pharmaceutical composition for the negative allosteric modulationof an mGluR2 receptor, and/or for treating one or more diseases orconditions listed above, comprising combining a compound (or compositioncomprising a compound) of the invention, or a stereoisomer thereof, or apharmaceutically acceptable salt of said compound or said stereoisomer,with a pharmaceutically acceptable carrier.

Combination Therapy

The compounds and compositions of the invention may be used incombination with one or more other drugs in the treatment of diseases orconditions for which the compounds of the invention have utility, wherethe combination of the drugs is desired, e.g., where the combination issafer or more effective than either drug alone. The compounds of theinvention may be used in combination with one or more other drugs thattreat, prevent, control, ameliorate, or reduce the risk of side effectsor toxicity of the compounds of the invention. Such other drugs may beadministered by a route and in an amount commonly used therefor,contemporaneously or sequentially with the compounds of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to the compounds of the present invention. Thecombinations may optionally be administered as part of a unit dosageform combination product, or as a kit or treatment protocol wherein oneor more additional drugs are administered in separate dosage forms aspart of a treatment regimen. In one embodiment, the compounds of theinvention useful in said combinations comprise a compound according toany one of Formulas (I), (IA), (IA-1), (IA-1a), (IA-1b), (IB), (IC), and(ID) as described herein, or according to any of the various embodimentsdescribed herein, or a stereoisomer thereof, or a pharmaceuticallyacceptable salt of said compound or said stereoisomer, or apharmaceutically acceptable composition thereof. In another embodiment,the compounds of the invention useful in said combinations comprise thecompounds of the examples, e.g., as set forth as example compounds ofthe invention. In another embodiment, the compounds of the inventionuseful in said combinations comprise the compound of example 2-5 or apharmaceutically acceptable salt of said compound, or a pharmaceuticallyacceptable composition thereof. In another embodiment, the compound ofthe invention useful in said combinations comprises the compound ofexample 2-3A or a pharmaceutically acceptable salt of said compound, ora pharmaceutically acceptable composition thereof. In anotherembodiment, the compound of the invention useful in said combinationscomprises the compound of example 2-3B or a pharmaceutically acceptablesalt of said compound, or a pharmaceutically acceptable compositionthereof. In another embodiment, the compound of the invention useful insaid combinations comprises the compound of example 3-1A or apharmaceutically acceptable salt of said compound, or a pharmaceuticallyacceptable composition thereof. In another embodiment, the compound ofthe invention useful in said combinations comprises the compound ofexample 3-1B or a pharmaceutically acceptable salt of said compound, ora pharmaceutically acceptable composition thereof. In anotherembodiment, the compound of the invention useful in said combinationscomprises the compound of example 3-7A or a pharmaceutically acceptablesalt of said compound, or a pharmaceutically acceptable compositionthereof. In another embodiment, the compound of the invention useful insaid combinations comprises the compound of example 3-7B or apharmaceutically acceptable salt of said compound, or a pharmaceuticallyacceptable composition thereof.

In another embodiment, a compound or composition of the invention may beemployed in combination with acetylcholinesterase inhibitors such asdonepezil and rivastigmine, NMDA antagonists such as memantine,muscarinic receptor modulators, AMPA receptor modulators, mGluR3receptor modulators, nicotinic alpha-7 and alpha-4-beta 2 receptormodulators, 5-HT6 and 5-HT4 receptor modulators, modulators ofphosphodiesterases (PDEs), alpha 2c receptor anagonists, histonedeacetylases, and antioxidant therapies.

In another embodiment, a compound or composition of the invention may beemployed in combination with therapies that may alter or modify thecourse of disease progression, including beta-amyloid modulatingtherapies such as BACE inhibitors, BACE antibodies, gamma-secretasemodulators, tau and/or phosphor-tau modulators, and biologic therapieswhich modulate placques associated with neurological disorders includingantibodies, RNAi, miRNA, and cell-therapies. Suitable BACE inhibitorsinclude but are not limited to verubecestat (Merck & Co., Inc.), AZD2392(Eli Lilly & Co./Astra Zeneca), CTS-21166 (CoMentis), E2609 (BiogenIdec, Inc./Esai Co., Ltd.), and BAN2401 (Biogen Idec, Inc./Esai Co.,Ltd.).

In another embodiment, a compound or composition of the invention may beemployed in combination with levodopa (with or without a selectiveextracerebral decarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide or pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.

Additional examples of combinations of the compounds includecombinations with agents for the treatment of pain, for examplenon-steroidal anti-inflammatory agents, such as aspirin, diclofenac,duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin,ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac andtolmetin; COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib,406381 and 644784; CB-2 agonists, such as 842166 and SAB378; VR-1antagonists, such as AMG517, 705498, 782443, PAC20030, V114380 andA425619; bradykinin B1 receptor antagonists, such as SSR240612 andNVPSAA164; sodium channel blockers and antagonists, such as VX409 andSPI860; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOSinhibitors), such as SD6010 and 274150; glycine site antagonists,including lacosamide; neuronal nicotinic agonists, such as ABT 894; NMDAantagonists, such as AZD4282; potassium channel openers; AMPA/kainatereceptor antagonists; calcium channel blockers, such as ziconotide andNMED160; GABA-A receptor IO modulators (e.g., a GABA-A receptoragonist); matrix metalloprotease (MMP) inhibitors; thrombolytic agents;opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol,meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine,propoxyphene; neutrophil inhibitory factor (NIF); pramipexole,ropinirole; anticholinergics; amantadine; monoamine oxidase B15(“MAO-B”) inhibitors; 5HT receptor agonists or antagonists; mGlu5antagonists, such as AZD9272; alpha agonists, such as AGNXX/YY; neuronalnicotinic agonists, such as ABT894; NMDA receptor agonists orantagonists, such as AZD4282; NKI antagonists; selective serotoninreuptake inhibitors (“SSRI”) and/or selective serotonin andnorepinephrine reuptake inhibitors (“SSNRI”), such as duloxetine;tricyclic antidepressant drugs, norepinephrine modulators; lithium;valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan;naratriptan and sumatriptan.

In another embodiment, the compounds and compositions of the inventionmay be administered in combination with compounds useful for thetreatment of schizophrenia or enhancing sleep quality and preventing andtreating sleep disorders and sleep disturbances, including e.g.,sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents,antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexinantagonists (such as suvorexant), orexin agonists, alpha-1 antagonists,GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and5HT-2A/2C antagonists, histamine antagonists including histamine H3antagonists, histamine H3 inverse agonists, imidazopyridines, minortranquilizers, melatonin agonists and antagonists, melatonergic agents,prokineticin agonists and antagonists, pyrazolopyrimidines, T-typecalcium channel antagonists, triazolopyridines, and the like, or thecompound of the present invention may be administered in conjunctionwith the use of physical methods such as with light therapy orelectrical stimulation.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like.

In one embodiment, the compound of the invention is administered duringa time when the additional therapeutic agent(s) exert their prophylacticor therapeutic effect, or vice versa.

In another embodiment, the compound of the invention and the additionaltherapeutic agent(s) are administered in doses commonly employed whensuch agents are used as monotherapy for treating the disorder.

In another embodiment, the compound of the invention and the additionaltherapeutic agent(s) are administered in doses lower than the dosescommonly employed when such agents are used as monotherapy for treatingthe disorder.

In one embodiment, the compound of the invention and the additionaltherapeutic agent(s) are present in the same composition, which issuitable for oral administration.

In some embodiments, the compound of the invention and the additionaltherapeutic agent(s) can act additively or synergistically. Asynergistic combination may allow the use of lower dosages of one ormore agents and/or less frequent administration of one or more agents ofa combination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of the therapy without reducingthe efficacy of the therapy.

The doses and dosage regimen of the additional therapeutic agent(s) usedin the combination therapies of the present invention for the treatmentor prevention of a disease or disorder can be determined by theattending clinician, taking into consideration the approved doses anddosage regimen in the package insert; the age, sex and general health ofthe patient; and the type and severity of the viral infection or relateddisease or disorder.

Another embodiment provides a kit comprising a therapeutically effectiveamount of the compound (or a composition comprising a compound) of theinvention, or a stereoisomer thereof, or a pharmaceutically acceptablesalt of said compound or said stereoisomer, optionally together with atleast one additional therapeutic agent listed above, and apharmaceutically acceptable carrier, vehicle or diluent.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like.

In one embodiment, the compound of the invention is administered duringa time when the additional therapeutic agent(s) exert their prophylacticor therapeutic effect, or vice versa.

In one embodiment, the compound of the invention and the additionaltherapeutic agent(s) are present in the same composition, which issuitable for oral administration.

PREPARATIVE EXAMPLES

In general, the compounds in the invention may be produced by a varietyof processes known to those skilled in the art and by known processesanalogous thereto. The invention disclosed herein is exemplified by thefollowing preparations and examples which should not be construed tolimit the scope of the disclosure. Alternative mechanistic pathways andanalogous structures will be apparent to those skilled in the art. Thepractitioner is not limited to these methods.

One skilled in the art will recognize that one route will be optimizeddepending on the choice of appendage substituents. Additionally, oneskilled in the art will recognize that in some cases the order of stepshas to be controlled to avoid functional group incompatability.

The prepared compounds may be analyzed for their composition and purityas well as characterized by standard analytical techniques such as, forexample, elemental analysis, NMR, mass spectroscopy and IR spectra.

One skilled in the art will recognize that reagents and solventsactually used may be selected from several reagents and solvents wellknown in the art to be effective equivalents. Hence, when a specificsolvent or reagent is mentioned, it is meant to be an illustrativeexample of the conditions desirable for that particular reaction schemeor for the preparation described below.

Where NMR data are presented, ¹H spectra were obtained on either aVarian 400, AVANCE III 400 or Varian AS500, and chemical shifts arereported as ppm with number of protons and multiplicities indicatedparenthetically. Where LC/MS data are presented, analyses was performedusing a Waters Acquity UPLC (BEH C18 column, 1.0×50 mm, 1.7 um, UV 254nm, 2 min 10-99% MeCN/water+0.05% TFA gradient, ESI positive) or anAgilent 1200 or Shimadzu 20AB series (with a Xtimate C18 column, 2.1×30mm, 3 um, UV 220 or 254 nm, 1.5 mL/4 L TFA in water (solvent A) and 0.75mL/4 L TFA in acetonitrile (solvent B), using the elution gradient10%-80% (solvent B) over 0.9 minutes and holding at 80% for 0.6 minutesat a flow rate of 1.2 mL/min, ESI positive).

Preparative chiral HPLC separations were generally carried out usingsupercritical fluid chromatography by eluting a chiral column such asOJ-H, (4.6×250 mm, Chiral Technologies, Inc., West Chester, Pa.) with amobile phase of isopropanol and supercritical CO2.

The following abbreviations may be used throughout the text:

Ac=acetyl; aq=aqueous; CO=carbon monoxide; Me=methyl; Et=ethyl;t-Bu:=tert-butyl; Ar:=aryl; Ph=phenyl; Bn=benzyl; EtOH=ethyl alcohol;IPA=isopropyl alcohol; AIBN=Azobisisobutyronitrile; ACN=acetonitrile;AcOK=potassium acetate; Boc=tert-butyloxycarbonyl;BOP:=benzotriazolyloxytris (dimethylamino) phosphoniumhexafluorophosphate; calcd (or calc'd)=calculated; chiralSFC=supercritical fluid chromatography on a chiral column;CIZn=Chlorozinc; DAST=diethylaminosulfur trifluoride;DCE=dichloroethane; DCM=dichloromethane;DCM/i-PrOH=dichloromethane/iso-propanol; DEA=diethylamine;DIBAL-H=diisobutylaluminium hydride; DIPEA=N,N-diisopropylethylamine;DMA=dimethylacetamide; DMEM=Dulbecco's Modified Eagle Medium (HighGlucose); DMF:=dimethylformamide; DMFDMA=N,N-dimethylformamidedimethylacetal; DMP=dess-martin periodinane; DMSO=dimethylsulfoxide;dppf=diphenylphosphorousferrocenyl; FBS=fetal bovine serum;HATU=N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate; (HCHO)_(n)=paraformaldehyde;HMDS=hexamethyldisilazane; HPLC=high performance liquid chromatography;m-CPBA=meta-chloroperoxybenzoic acid; M=molar; m-CPBA (ormCPBA)=meta-chloroperoxybenzoic acid; MS=mass spectrometry; MS (ESI)calcd=mass spec (Electrospray ionization); Ms=mesyl; NMO=N-methylmorpholine N-oxide;Pd(dtbpf)Cl2=1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II);PMB=p-methoxybenzyl; Prep-TLC=preparative thin layer chromatography;rt=room temperature; SFC=supercritical fluid chromatography;TEA=triethylamine; TFA=trifluoroacetic acid; THF=tetrahydrofuran;TPAP=tetra-n-propyl ammonium perruthenate.

The following intermediate compounds were prepared as described belowfor use in the preparation of compounds of the invention.

Intermediate 2-1

2,6-dichloro-4-(2,4-difluorophenyl)nicotinaldehyde Step 1:4-bromo-2,6-dichloronicotinic acid

n-Butyllithium (38.8 mL, 97 mmol) was added dropwise to diisopropylamine(14.91 mL, 106 mmol) in THF (50 mL) at −78° C. The solution was stirredat −78° C. for 0.5 h and at 0° C. for 0.5 h. The crude pale yellowsolution of lithium diisopropylamide was used in the next step withoutfurther purification.

To a stirred and cooled (−78° C.) solution of4-bromo-2,6-dichloropyridine (20 g, 88 mmol) in THF (550 mL) was addeddropwise the pre-formed solution of lithium diisopropylamide under N₂atmosphere. The mixture was stirred at −78° C. for 1 h, (dry ice) carbondioxide (50 g, 1136 mmol) was added to the reaction mixture at −78° C.and stirred for 1 h. 1 M aqueous Na₂CO₃ (1 L) was added to quench thereaction. The mixture was extracted with ethyl acetate (1 L), theaqueous solution was acidified with 1M aqueous HCl to pH˜4. The mixturewas extracted with ethyl acetate (2×1 L). The combined organic phaseswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto give the product which was used in subsequent steps without furtherpurification. MS (ESI) calcd for (C₆H₃BrCl₂NO₂) [M+H]⁺, [271.86], found,[271.7].

¹H NMR (400 MHz, DMSO-d₆) δ 8.48-7.66 (m, 1H)

Step 2: (trimethylsilyl)methyl 4-bromo-2,6-dichloronicotinate and methyl4-bromo-2,6-dichloronicotinate

To a solution of 4-bromo-2,6-dichloronicotinic acid (19.5 g, 72.0 mmol)in THF (500 mL) was added dropwise (trimethylsilyl)diazomethane (54.0mL, 108 mmol) at 15° C. The mixture was stirred at 15° C. for 8 h. Themixture was quenched with HCl (2M) (20 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography (ISCO®; 120 g SepaFlash® Column, elutingwith 0 to 5% ethyl acetate/petroleum ether) to give a mixture of theproducts. MS (ESI) calcd for (C₁₀H₁₃BrCl₂NO₂Si) [M+H]⁺, 357.9, found,357.8. MS (ESI) calcd for (C₇H₅BrCl₂NO₂) [M+H]⁺, 285.9, found, 285.8.

Step 3: 4-bromo-2,6-dichloronicotinaldehyde

To a solution of (trimethylsilyl)methyl 4-bromo-2,6-dichloronicotinateand methyl 4-bromo-2,6-dichloronicotinate (17 g, ˜60 mmol) in toluene(400 mL) was added dropwise DIBAL-H (65.6 mL, 65.6 mmol) at −78° C. Themixture was stirred at −78° C. for 2 h. The mixture was quenched withsaturated aqueous NH₄Cl (300 mL). Aqueous HCl (2M, 150 mL) was added andthe mixture was extracted with ethyl acetate (2×500 mL), the combinedorganics were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography (ISCO®;120 g SepaFlash® Column, eluting with 0 to 3% ethyl acetate/petroleumether) to give the product. ¹H NMR (400 MHz, CDCl₃) δ 10.36 (s, 1H),7.77-7.63 (m, 1H)

Step 4: 2,6-dichloro-4-(2,4-difluorophenyl)nicotinaldehyde

A mixture of (2,4-difluorophenyl)boronic acid (4.52 g, 28.6 mmol),4-bromo-2,6-dichloronicotinaldehyde (7.3 g, 28.6 mmol) and Na₂CO₃ (6.07g, 57.3 mmol) in 1,4-dioxane (120 mL) and water (12 mL) was addedPdCl₂(dppf) (1.0 g, 1.4 mmol) under N₂. The mixture was heated to 100°C. for 2 h. After cooling to 20° C., the mixture was poured into water(500 mL) and extracted with ethyl acetate (2×500 mL), the combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(ISCO®; 80 g SepaFlash® Column, eluting with 0 to 3% ethylacetate/petroleum ether) to give the title compound. ¹H NMR (400 MHz,CDCl₃) δ 10.34 (s, 1H), 7.29-7.19 (m, 2H), 7.01 (dt, J=1.5, 8.3 Hz, 1H),6.95-6.86 (m, 1H)

Intermediate 2-2

ethyl(E)-4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-oxobut-3-enoate

See procedure for Example 2-1A and 2-1B, Step 1

Intermediate 2-3

ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-hydroxybutanoate

See procedure for Example 2-1A and 2-1B, Step 2

Intermediate 2-4

ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

See procedure for Example 2-1A and 2-1B, Step 5

Intermediates 2-5A, 2-5B, 2-5C and 2-5D

ethyl(2S,3R)-5-(2,4-difluoropheny)-2-(hydroxmethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate,ethyl(2S,3S)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate,ethyl(2R,3R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(2R,3S)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

See procedure for Example 2-2A, 2-2B, 2-2C and 2-2D, Step 8

Intermediate 2-6

methyl 3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propanoate

See procedure for Example 2-3A and 2-3B, Step 3

Intermediate 2-7

3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propanal

See procedure for Example 2-3A and 2-3B, Step 5

Intermediate 3-1

ethyl5-(2,4-difluorophenyl)-2-formyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

See procedure for Example 3-7A and 3-7B, Step 1

Intermediate 3-2

7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxylicacid

See procedure for Example 2-9A, 2-9B, 2-9C and 2-9D, Step 1

Compounds of Formula I (where in Scheme 1 X is a bridge of twomethylenes or is not present, ring B, n, and each R¹ are as defined inFormula I, and R and R′ are H or methyl) may be prepared according toScheme 1 by the amination of aldehyde 1-1 followed by acylation andcyclization of 1-3 to form pyridine 1-4. Pyridine 1-4 is sequentiallydeacylated, chlorinated and carbonylated to generate chloropyridine 1-7.Chloropyridine 1-7 can either be coupled directly with an aromaticboronic acid, or itself be converted to a boronic acid 1-7a and coupledto an aromatic bromide, to form 1-8 which is treated with ammonia tofurnish 1-9.

Example 1-1

4-(2,4-difluorophenyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridine-2-carboxamideStep 1: Ethyl 5-amino-3,6-dihydro-2H-pyran-4-carboxylate

A mixture of methyl5-(3-methoxy-3-oxopropyl)tetrahydrofuran-2-carboxylate (3 g, 17.4 mmol)and NH₄OCONH₂ (2.65 g, 34.9 mmol) in MeOH (20 mL) was stirred at 25° C.for 2 h. The mixture was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting with 5:1petroleum ether/ethyl acetate) to give the product. ¹H NMR (400 MHz,CD₃OD) δ 4.17-4.03 (m, 4H), 3.73 (t, J=5.5 Hz, 2H), 2.37-2.19 (m, 2H),1.24 (t, J=7.0 Hz, 3H).

Step 2: ethyl5-(3-methoxy-3-oxopropanamido)-3,6-dihydro-2H-pyran-4-carboxylate

Ethyl 5-amino-3,6-dihydro-2H-pyran-4-carboxylate (2.6 g, 15 mmol) andEt₃N (6 mL, 45 mmol) were dissolved in DCM (50 mL), methyl3-chloro-3-oxopropanoate (2.26 g, 16 mmol) was added and the resultingsolution was stirred for 2 h at 0° C. The mixture was quenched withwater (30 mL) and extracted with DCM (3×40 mL). The combined organiclayers were washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(eluting with 10:1 petroleum ether/ethyl acetate) to give the product.MS (ESI) calcd. for (C₁₂H₁₈NO₆) [M+H]⁺, 272.1, found, 271.9. ¹H NMR (400MHz, CDCl₃) δ 4.77 (s, 1H), 4.17 (q, J=7.0 Hz, 1H), 3.79-3.63 (m, 3H),3.35 (s, 1H), 2.38 (t, J=5.3 Hz, 1H), 1.24 (t, J=7.0 Hz, 3H).

Step 3: Methyl2,4-dihydroxy-6,8-dihydro-5H-pyrano[3,4-b]pyridine-3-carboxylate

Ethyl 5-(3-methoxy-3-oxopropanamido)-3,6-dihydro-2H-pyran-4-carboxylate(1.15 g, 4 mmol) was dissolved in MeOH (15 mL), sodium methanolate (0.25g, 4.6 mmol) was added and the resulting solution was stirred for 1 h at80° C. The mixture was concentrated under reduced pressure to afford theproduct which was used in the next step without further purification. MS(ESI) calcd. for (C₁₀H₁₂NO₅) [M+H]⁺, 225.0, found, 225.9. ¹H NMR (400MHz, CD₃OD) δ 4.18-4.03 (m, 3H), 3.73 (t, J=5.7 Hz, 2H), 2.27 (t, J=5.7Hz, 2H), 1.24 (t, J=7.0 Hz, 2H).

Step 4: 6,8-dihydro-5H-pyrano[3,4-b]pyridine-2,4-diol

Aqueous HCl (6 M, 20 mL, 120 mmol) was added to methyl2,4-dihydroxy-6,8-dihydro-5H-pyrano[3,4-b]pyridine-3-carboxylate (1 g,crude) and the mixture was stirred at 100° C. for 4 h. The solvent wasremoved under reduced pressure to give the product which was used in thenext step without further purification. MS (ESI) calcd. for (C₈H₁₀NO₃)[M+H]⁺, 168.0, found, 167.8.

Step 5: 2,4-dichloro-6,8-dihydro-5H-pyrano[3,4-b]pyridine

A mixture of 6,8-dihydro-5H-pyrano[3,4-b]pyridine-2,4-diol (0.9 g,crude) and DMF (5 mL, 64 mmol) in phosphoryl trichloride (4.3 mL, 48.5mmol) was stirred at 80° C. for 12 h. The mixture was allowed to cool toroom temperature and poured into ice-water and the mixture was adjustedto pH 9 with saturated aqueous Na₂CO₃. The mixture was extracted withEtOAc (3×50 mL). The combined organic layers were washed with brine (45mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel chromatography (eluting with 100:0 to 20:1petroleum ether/ethyl acetate) to give the product. MS (ESI) calcd. for(C₈H₈Cl₂NO) [M+H]⁺, 204.0, found, 203.9. ¹H NMR (400 MHz, CDCl₃) δ 7.29(s, 1H), 5.10 (d, J=6.4 Hz, 1H), 4.86 (br. s., 1H), 3.24-3.12 (m, 2H),2.52 (d, J=17.4 Hz, 2H), 2.11 (t, J=9.6 Hz, 2H).

Step 6: ethyl4-chloro-6,8-dihydro-5H-pyrano[3,4-b]pyridine-2-carboxylate

To a solution of 2,4-dichloro-6,8-dihydro-5H-pyrano[3,4-b]pyridine (100mg, 0.49 mmol) in EtOH (20 mL) was added potassium acetate (96 mg, 0.98mmol) and PdCl₂(dppf) (36 mg, 0.049 mmol) under N₂. The mixture wasdegassed and backfilled with CO (three times). The resulting mixture wasstirred under 50 psi of CO at 60° C. for 1.5 h. The mixture wasconcentrated under reduced pressure to give the crude product, which waspurified by silica gel chromatography (ISCO®; 40 g SepaFlash® Column,eluting with 0 to 20% ethyl acetate/petroleum ether at 40 mL/min) tofurnish the product. MS (ESI) calcd. for (C₁₁H₁₂ClNO₃) [M+H]⁺, 242.0,found, 241.9. ¹H NMR (400 MHz, CD₃OD) δ 8.00 (s, 1H), 4.75 (s, 2H), 4.41(q, J=7.2 Hz, 2H), 4.01 (t, J=5.9 Hz, 2H), 2.93 (t, J=5.7 Hz, 2H), 1.39(t, J=7.2 Hz, 3H).

Step 7: Ethyl4-(2,4-difluorophenyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridine-2-carboxylate

To a mixture of ethyl4-chloro-6,8-dihydro-5H-pyrano[3,4-b]pyridine-2-carboxylate (100 mg,0.613 mmol), (2,4-difluorophenyl)boronic acid (260 mg, 1.65 mmol) andK₃PO₄ (263 mg, 1.24 mmol) in THF (4.5 mL) and water (0.5 mL) was addedPdCl₂(dppf) (51 mg, 0.082 mmol), and the mixture was degassed andbackfilled with N₂ (three times). The mixture was heated to 80° C. for 2h. The mixture was concentrated under reduced pressure to give the crudeproduct, which was purified by Prep-TLC (silica gel, eluting with 1:1ethyl acetate/petroleum ether) to give the product. MS (ESI) calcd. for(C₁₇H₁₆F₂NO₃) [M+H]⁺, 320.1, found, 319.9. ¹H NMR (400 MHz, CD₃OD) δ7.85 (s, 1H), 7.46-7.34 (m, 1H), 7.13 (q, J=7.7 Hz, 2H), 4.41 (q, J=7.0Hz, 2H), 4.03-3.85 (m, 2H), 2.80-2.66 (m, 2H), 1.39 (t, J=7.2 Hz, 3H).

Step 8:4-(2,4-difluorophenyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridine-2-carboxamide

A mixture of ethyl4-(2,4-difluorophenyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridine-2-carboxylate(80 mg, 0.25 mmol) in NH₃ in MeOH (15 mL, 150 mmol) was stirred at 25°C. for 12 h. The mixture was concentrated under reduced pressure andpurified by Prep-HPLC (Column: Agela ASB 150×25 mm, 5 um; Mobile phase:30% to 60% water (containing 0.1% TFA)-ACN; Flow rate: 25 mL/min) togive the title compound. MS (ESI) calcd. for (C₁₅H₁₄F₂N₂O₂) [M+H]⁺,291.1, found, 291.0. ¹H NMR (400 MHz, CD₃OD) δ 7.82 (s, 1H), 7.44-7.32(m, 1H), 7.18-7.05 (m, 2H), 3.93 (t, J=5.7 Hz, 2H), 2.70 (t, J=5.3 Hz,2H).

Example 1-2A and 1-2B

(6S,9R)-4-(2,4-difluorophenyl)-6,7,89-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxamideand(6R,9S)-4-(2,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxamideStep 1: methyl 5-(3-methoxy-3-oxopropyl)furan-2-carboxylate

A mixture of methyl 5-bromofuran-2-carboxylate (10 g, 64 mmol), methylacrylate (16.5 g, 192 mmol), (MeO)₃P (0.4 g, 0.32 mmol), Et₃N (17 mL,128 mmol) and Pd(OAc)₂ (0.36 g, 0.16 mmol) in DMF (120 mL) was degassedand backfilled with N₂ (three times). The mixture was heated to 110° C.for 3 h. The cooled mixture was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with 5:1 petroleum ether/ethyl acetate) togive the product. ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J=15.9 Hz, 1H),7.20 (d, J=3.5 Hz, 1H), 6.68 (d, J=3.5 Hz, 1H), 6.57 (d, J=15.9 Hz, 1H),3.92 (s, 3H), 3.81 (s, 3H).

Step 2: methyl 5-(3-methoxy-3-oxopropyl)tetrahydrofuran-2-carboxylate

To a solution of methyl 5-(3-methoxy-3-oxopropyl)furan-2-carboxylate(4.7 g, 22 mmol) in ethyl acetate (100 mL) was added Pd/C (1 g) (10% wt)under N₂ atmosphere. The mixture was degassed and backfilled with H₂(three times). The resulting mixture was stirred under 40 psi of H₂ at50° C. for 15 h. The mixture was filtered and the filtrate wasconcentrated under reduced pressure to give the product which was usedin subsequent steps without further purification. ¹H NMR (400 MHz,CDCl₃) δ 4.42 (dd, J=5.0, 8.5 Hz, 1H), 4.07-3.95 (m, 1H), 3.74-3.67 (m,3H), 3.64 (s, 3H), 2.57-2.36 (m, 2H), 2.20 (qd, J=8.4, 12.6 Hz, 1H),2.11-1.81 (m, 5H), 1.58 (qd, J=8.2, 11.9 Hz, 1H).

Step 3: methyl 2-oxo-8-oxabicyclo[3.2.1]octane-3-carboxylate

To a mixture of methyl5-(3-methoxy-3-oxopropyl)tetrahydrofuran-2-carboxylate (4.6 g, 21 mmol)in THF (60 mL) was added NaH (840 mg, 60% in oil) slowly under N₂ andthe mixture was heated at reflux for 6 h. The reaction was quenched withNH₄Cl (50 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine (60 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (eluting with 5:1 petroleumether/ethyl acetate) to give the product. ¹H NMR (400 MHz, CDCl₃) δ4.65-4.48 (m, 1H), 4.41-4.22 (m, 1H), 3.75-3.64 (m, 1H), 2.69 (dd,J=4.9, 15.7 Hz, 1H), 2.40-2.29 (m, 1H), 2.18-2.01 (m, 3H), 1.94-1.72 (m,2H).

Step 4: methyl 2-amino-8-oxabicyclo[3.2.1]oct-2-ene-3-carboxylate

A mixture of methyl 2-oxo-8-oxabicyclo[3.2.1]octane-3-carboxylate (200mg, 1.08 mmol) and NH₄OAc (770 mg, 10 mmol) in MeOH was stirred in asealed tube at 90° C. for 15 h. The mixture was concentrated underreduced pressure. The residue was dissolved in water (10 mL) andextracted with ethyl acetate (5×15 mL). The combined organic layers werewashed with brine (30 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (eluting with 5:1 petroleum ether/ethyl acetate) to givethe product. ¹H NMR (400 MHz, CDCl₃) δ 4.52 (t, J=5.0 Hz, 1H), 4.38 (br.s., 1H), 3.52 (s, 3H), 2.56 (d, J=5.3 Hz, 1H), 2.00-1.82 (m, 5H), 1.58(t, J=8.2 Hz, 1H).

Step 5: Methyl2-(3-ethoxy-3-oxopropanamido)-8-oxabicyclo[3.2.1]oct-2-ene-3-carboxylate

Methyl 2-amino-8-oxabicyclo[3.2.1]oct-2-ene-3-carboxylate (490 mg, 2.67mmol) and Et₃N (0.7 mL, 5.3 mmol) were dissolved in DCM (20 mL),ethyl-3-chloro-3-oxopropanoate (481 mg, 3.1 mmol) was added and theresulting solution was stirred for 2 h at 20° C. The mixture wasquenched with water (15 mL) and extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography (eluting with 4:1 petroleum ether/ethyl acetate) togive the product. MS (ESI) calcd. for (C₁₄H₂₀NO₆) [M+H]⁺, 298.1, found,298.1.

Step 6: methyl2,4-dihydroxy-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-3-carboxylate

Methyl2-(3-ethoxy-3-oxopropanamido)-8-oxabicyclo[3.2.1]oct-2-ene-3-carboxylate(4.8 g, 16 mmol) was dissolved in MeOH (80 mL), sodium methanolate (368mg, 16.1 mmol) was added and the resulting solution was stirred for 1.5h at 80° C. The cooled mixture was filtered and concentrated underreduced pressure to afford the product which was used in the next stepwithout further purification. MS (ESI) calcd. for (C₁₂H₁₄NO₅) [M+H]⁺,252.1, found, 252.0.

Step 7: 6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2,4-diol

Aqueous HCl (20 mL, 120 mmol, 6 M) was added to methyl2,4-dihydroxy-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-3-carboxylate(1.2 g, 4.8 mmol) and the mixture was stirred at 100° C. for 20 h. Themixture was extracted with 3:1 DCM/i-PrOH (4×100 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give the product which was used in the next stepwithout further purification. MS (ESI) calcd. for (C₁₀H₁₁NO₃) [M+H]⁺,194.1, found, 193.9.

Step 8:2,4-dichloro-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine

A mixture of6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2,4-diol (1.2 g,6.21 mmol) and DMF (6.5 mL, 6.21 mmol) in phosphoryl trichloride (8.48g, 55.3 mmol) was stirred at 90° C. for 15 h. DMF (0.2 mL) was added andthe mixture was stirred at 90° C. for 15 h. The cooled mixture waspoured into ice-water and the pH was adjusted to 7 with Sat'd. NaHCO₃.The mixture was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine (45 mL), dried over Na₂SO₄,filtered and concentrated, the residue was purified by silica gelchromatography (eluting with 4:1 petroleum ether/ethyl acetate) to givethe product. MS (ESI) calcd. for (C₁₀H₁₀Cl₂NO) [M+H]⁺, 230.0, found,230.1. ¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H), 5.10 (d, J=6.4 Hz, 1H),4.86 (br. s., 1H), 3.24-3.12 (m, 2H), 2.52 (d, J=17.4 Hz, 2H), 2.11 (t,J=9.6 Hz, 2H).

Step 9: ethyl4-chloro-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylate

To a solution of2,4-dichloro-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine (330mg, 1.434 mmol) in EtOH (10 mL) was added potassium acetate (282 mg,2.87 mmol) and PdCl₂(dppf) (105 mg, 0.143 mmol) under N₂ atmosphere. Themixture was degassed and backfilled with CO (three times). The resultingmixture was stirred under 50 psi of CO at 80° C. for 2 h. The mixturewas concentrated under reduced pressure to give the crude product, whichwas purified by silica gel chromatography (ISCO®; 40 g SepaFlash®Column, eluting with 0 to 20% ethyl acetate/petroleum ether) to furnishthe product. MS (ESI) calcd. for (C₁₃H₁₅ClNO₃) [M+H]⁺, 268.1, found,268.1.

Step 10: ethyl4-(2,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylate

To a mixture of ethyl4-chloro-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylate(140 mg, 0.523 mmol), (2,4-difluorophenyl)boronic acid (165 mg, 1.046mmol) and K₂CO₃ (145 mg, 1.046 mmol) in 1,4-dioxane (5 mL) and water(0.5 mL) was added PdCl₂(dppf) (38.3 mg, 0.052 mmol). The mixture wasdegassed and backfilled with N₂ (three times) then heated to 100° C. for2 h. The mixture was concentrated under reduced pressure to give thecrude product, which was purified by silica gel chromatography (ISCO®;40 g SepaFlash® Column, eluting with of 0 to 30% ethyl acetate/petroleumether) to give the product. MS (ESI) calcd. for (C₁₉H₁₈F₂NO₃) [M+H]⁺,346.1, found, 346.0. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.21 (d,J=6.26 Hz, 1H), 6.91-7.06 (m, 2H), 5.37 (d, J=6.26 Hz, 1H), 4.73-4.80(m, 1H), 4.49 (d, J=7.04 Hz, 2H), 3.12-3.22 (m, 1H), 2.20-2.36 (m, 4H),1.57-1.76 (m, 2H), 1.43 (t, J=7.04 Hz, 3H).

Step 11: ethyl(6S,9R)-4-(2,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylateand ethyl(6R,9S)-4-(2,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylate

Racemic ethyl4-(2,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylate(100 mg, 0.290 mmol) was resolved via chiral SFC (Column: Chiralpak AD250×30 mm, 5 um; Mobile phase: 15% to 15% EtOH (containing 0.05% DEA) inCO₂; Flow rate: 60 mL/min) to give the two enantiomers.

Step 12:(6S,9R)-4-(2,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxamideand(6R,9S)-4-(2,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxamide

One enantiomer of ethyl4-(2,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylate(40 mg, 0.116 mmol) was mixed with ammonia in MeOH (15 mL, 150 mmol) andstirred at 20° C. for 17 h. The mixture was concentrated under reducedpressure to give one enantiomer of the title compound. MS (ESI) calcd.for (C₁₇H₁₅F₂N₂O₂) [M+H]⁺, 317.1, found, 317.0. ¹H NMR (400 MHz, CD₃OD)δ 7.82 (s, 1H), 7.31-7.41 (m, 1H), 7.07-7.18 (m, 2H), 5.17 (d, J=5.95Hz, 1H), 4.75 (t, J=5.84 Hz, 1H), 3.11 (br. s., 1H), 2.03-2.39 (m, 5H),1.69 (br. s., 1H).

Similar treatment of the other enantiomer of ethyl4-(2,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylateafforded the other enantiomer of the title compound. MS (ESI) calcd. for(C₁₇H₁₅F₂N₂O₂) [M+H]⁺, 317.1, found, 317.0. ¹H NMR (400 MHz, CD₃OD) δ7.81 (s, 1H), 7.36 (d, J=6.39 Hz, 1H), 7.07-7.18 (m, 2H), 5.17 (d,J=5.95 Hz, 1H), 4.74 (br. s., 1H), 3.12 (dd, J=17.42, 5.29 Hz, 1H),2.03-2.39 (m, 4H), 1.62-1.72 (m, 1H).

The following compounds were prepared according to the proceduresdescribed above.

MS MS Ex- (ESI) (ESI) ample Structure Name calcd found ¹H NMR 1-3A

(6S,9R)- or (6R,9S)- 4-(4-chloro-2- fluorophenyl)-6,7,8,9-tetrahydro-5H-6,9- epoxycyclo- hepta[b]pyridine-2- carboxamide 333.07333.0 (400 MHz, CD₃OD)δ 7.85 (s, 1H), 7.33-7.45 (m, 3H), 5.21 (d, J =5.87 Hz, 1H), 4.78 (t, J = 5.48 Hz, 1H), 3.15 (dd, J = 17.61, 5.09 Hz,1H), 2.37 (d, J = 17.22 Hz, 1H), 2.17-2.31 (m, 2H), 2.08-2.16 (m, 1H),1.66- 1.78 (m, 1H). 1-3B

(6R,9S)- or (6S,9R)- 4-(4-chloro-2- fluorophenyl)-6,7,8,9-tetrahydro-5H-6,9- epoxycyclo- hepta[b]pyridine-2- carboxamide 333.07333.0 (400 MHz, CD₃OD)δ 7.45 (s, 1H), 6.92-7.04 (m, 3H), 4.80 (d, J =5.87 Hz, 1H), 4.38 (t, J = 5.67 Hz, 1H), 2.75 (dd, J = 17.41, 5.28 Hz,1H), 1.96 (d, J = 17.61 Hz, 1H), 1.79-1.91 (m, 2H), 1.68-1.75 (m, 1H),1.25- 1.37 (m, 1H). 1-4A

(6R,9S)- or (6S,9R)- 4-(1-methyl-1H- pyrazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9- epoxycyclo- hepta[b]pyridine-2- carboxamide 285.1285.1 (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.89 (br. s., 1H), 7.82 (s, 1H),7.72 (s, 1H), 5.88 (br. s., 1H), 5.14 (d, J = 5.73 Hz, 1H), 4.78-4.96(m, 1H), 3.99 (s, 3H), 3.41 (dd, J = 5.18, 16.87 Hz, 1H), 2.59 (d, J =16.76 Hz, 1H), 2.17-2.37 (m, 2H), 1.99- 2.13 (m, 1H), 1.55-1.76 (m, 1H).1-4B

(6S,9R)- or (6R,9S)- 4-(1-methyl-1H- pyrazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9- epoxycyclo- hepta[b]pyridine-2- carboxamide 285.1285.1 (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.97 (br. s., 1H), 7.83 (s, 1H),7.73 (s, 1H), 6.29 (br. s., 1H), 5.15 (d, J = 5.51 Hz, 1H), 4.73-4.99(m, 1H), 4.00 (s, 3H), 3.41 (dd, J = 5.18, 16.87 Hz, 1H), 2.60 (d, J =16.98 Hz, 1H), 2.17-2.36 (m, 2H), 1.98- 2.14 (m, 1H), 1.53-1.76 (m, 1H).1-5A

(6R,9S)- or (6S,9R)- 4-(1- (difluoromethyl)- 1H-pyrazol-4-yl)-6,7,8,9-tetrahydro- 5H-6,9-epoxycyclo- hepta[b]pyridine-2- carboxamide321.1 321.1 (400 MHz, CDCl₃) δ 8.12 (s, 2H), 8.04 (br. s., 1H), 7.98 (s,1H), 7.42 (s, 0.24H), 7.25-7.27 (m, 0.52H), 7.12 (s, 0.24H), 6.74 (br.s., 1H), 5.19 (d, J = 5.73 Hz, 1H), 4.76-5.02 (m, 1H), 3.44 (dd, J =5.29, 16.98 Hz, 1H), 2.60 (d, J = 16.98 Hz, 1H), 2.19-2.43 (m, 2H),1.95- 2.15 (m, 1H), 1.54-1.78 (m, 1H). 1-5B

(6S,9R)- or (6R,9S)- 4-(1- (difluoromethyl)- 1H-pyrazol-4-yl)-6,7,8,9-tetrahydro- 5H-6,9-epoxycyclo- hepta[b]pyridine-2- carboxamide321.1 321.1 (400 MHz, CDCl₃) δ 8.12 (d, J = 3.09 Hz, 2H), 7.98 (s, 2H),7.42 (s, 0.24H), 7.25-7.27 (m, 0.54H), 7.12 (s, 0.24H), 6.36 (br. s.,1H), 5.18 (d, J = 5.95 Hz, 1H), 4.78-4.98 (m, 1H), 3.44 (dd, J = 5.29,16.98 Hz, 1H), 2.60 (d, J = 16.98 Hz, 1H), 2.19-2.43 (m, 2H), 1.98- 2.15(m, 1H), 1.60-1.79 (m, 1H).

Example 1-6A and 1-6B

(6S,9R)-4-(3,5-difluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxamideand(6R,9S)-4-(3,5-difluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxamideStep 1:(2-(ethoxycarbonyl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridin-4-yl)boronicacid

A mixture of ethyl4-chloro-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylate(Example 1-2 Step 9) (200 mg, 0.75 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1900 mg,7.5 mmol), Pd(dtbpf)Cl₂ (48.7 mg, 0.08 mmol) and AcOK (220 mg, 2.2 mmol)in 1,4-dioxane (5 mL) was stirred at 100° C. under N₂ for 2 h. Themixture was concentrated under reduced pressure. The residue waspurified by Prep-HPLC (Column: Waters Xbridge Prep OBD C18 100×19 mm, 5um; Mobile phase: 28% to 58% water (containing 0.05% ammonia hydroxidev/v)-ACN; Flow rate: 25 mL/min) to give the product. MS (ESI) calcd. for(C₁₃H₁₇BNO₅) [M+H]⁺, 278.1, found, 277.9.

Step 2: Ethyl4-(3,5-difluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylate

A mixture of(2-(ethoxycarbonyl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridin-4-yl)boronicacid (100 mg, 0.361 mmol), 2-bromo-3,5-difluoropyridine (140 mg, 0.722mmol), Pd(dtbpf)Cl₂ (23.5 mg, 0.04 mmol) and K₃PO₄ (230 mg, 1.08 mmol)in THF (5 mL) and H₂O (1 mL) was stirred at 80° C. under N₂ for 2 h. Themixture was concentrated under reduced pressure, and purified byPrep-HPLC (Column: Phenomenex Synergi C18 150×30 mm, 4 um; Mobile phase:41% to 61% water (containing 0.1% TFA)-ACN; Flow rate: 25 mL/min) togive the product. MS (ESI) calcd. for (C₁₈H₁₇F₂N₂O₃) [M+H]⁺, 347.1,found, 346.9.

Step 3: ethyl(6R,9S)-4-(3,5-difluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylateand ethyl(6S,9R)-4-(3,5-difluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylate

Racemic ethyl4-(3,5-difluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylate(30 mg, 0.087 mmol) was resolved by chiral SFC (Column: Chiralpak AD250×30 mm, 10 um; Mobile phase: 45% EtOH (containing 0.05% DEA) in CO₂;Flow rate: 80 mL/min) to give the two enantiomers.

Step 4:(6R,9S)-4-(3,5-difluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxamideand(6S,9R)-4-(3,5-difluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxamide

A solution of one enantiomer of ethyl4-(3,5-difluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylate(12 mg, 0.035 mmol) in ammonia (10M in MeOH) (20 mL) was stirred at 26°C. for 12 h. The mixture was concentrated under reduced pressure andpurified by Prep-HPLC (Column: Phenomenex Synergi C18 150×30 mm, 4 um;Mobile phase: 25% to 45% water (containing 0.1% TFA)-ACN; Flow rate: 25mL/min) to give one enantiomer of the title compound. MS (ESI) calcd.for (C₁₆H₁₄F₂N₃O₂) [M+H]⁺, 318.1, found, 317.9. ¹H NMR (400 MHz, CD₃OD)δ 8.53 (s, 1H), 7.96 (s, 1H), 7.79 (t, J=8.38 Hz, 1H), 5.19 (d, J=5.95Hz, 1H), 4.68-4.79 (m, 1H), 3.25 (dd, J=5.40, 17.75 Hz, 1H), 2.48 (d,J=17.86 Hz, 1H), 2.07-2.32 (m, 4H), 1.71 (br. s., 1H).

Similar treatment of the other enantiomer of ethyl4-(3,5-difluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxylateafforded the other enantiomer of the title compound. MS (ESI) calcd. for(C₁₆H₁₄F₂N₃O₂) [M+H]⁺, 318.1, found, 317.9. ¹H NMR (400 MHz, CD₃OD) δ8.53 (s, 1H), 7.97 (s, 1H), 7.79 (t, J=8.16 Hz, 1H), 5.19 (d, J=5.51 Hz,1H), 4.65-4.80 (m, 1H), 3.20-3.27 (m, 1H), 2.48 (d, J=17.42 Hz, 1H),2.16-2.31 (m, 2H), 2.05-2.16 (m, 1H), 1.71 (br. s., 1H).

Example 1-7A and 1-7B

(6S,9R)-4-(5-chloro-3-fluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxamideand(6R,9S)-4-(5-chloro-3-fluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epoxycyclohepta[b]pyridine-2-carboxamide

The title compounds were prepared according to the same procedure asExample 1-6A and 1-6B, substituting 2-bromo-5-chloro-3-fluoropyridinefor 2-bromo-3,5-difluoropyridine.

Enantiomer 1: MS (ESI) calcd. for (C₁₆H₁₃ClFN₃O₂) [M+H]⁺, 334.07, found,333.8. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.94-8.00 (m, 2H), 5.18(d, J=5.87 Hz, 1H), 4.73 (t, J=5.67 Hz, 1H), 3.20-3.26 (m, 1H), 2.48 (d,J=17.61 Hz, 1H), 2.17-2.27 (m, 2H), 2.08 (t, J=9.78 Hz, 1H), 1.63-1.75(m, 1H).

Enantiomer 2: MS (ESI) calcd. for (C₁₆H₁₃ClFN₃O₂) [M+H]⁺, 334.07, found,333.8. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.93-8.00 (m, 2H), 5.17(d, J=6.26 Hz, 1H), 4.73 (t, J=5.87 Hz, 1H), 3.24 (dd, J=17.80, 5.28 Hz,1H), 2.47 (d, J=18.00 Hz, 1H), 2.12-2.30 (m, 2H), 2.04-2.12 (m, 1H),1.63-1.75 (m, 1H).

Compounds of Formula I (where, in Scheme 2, R², R^(2A), R³, R^(3A), ringB, n, and each R¹ are as described in Formula I, and wherein R^(2x),R^(2y) R^(3x), R^(3y) correspond to R², R^(2A), R³, R^(3A), or can beconverted by methods known to those skilled in the art to R², R^(2A) R³,R^(3A), respectively) may be prepared according to Scheme 2 by a Wittigreaction with aldehyde 2-1 followed by reduction (and/or addition asappropriate) and cyclization of 2-3 to form bicycle 2-4. Alternatively,2-3 can be formed via an alkylation of the aldehyde 2-1 followed byradical deoxygenation and subsequent reduction (and/or addition asappropriate). Bicycle 2-4 is sequentially carbonylated and treated withammonia to furnish 2-6. Reactions on the carbon chain of 2-2 and 2-3and/or on the R^(2x), R^(2y) R^(3x), R^(3y) group of 2-2, 2-2a, 2-3 or2-4 can be used to make further changes to the bicyclic core orsubstituents thereof.

Example 2-1A and 2-1B

(S)-5-(2,4-difluorophenyl)-2-(hydroxmethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: ethyl(E)-4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-oxobut-3-enoate(Intermediate 2-2)

To a stirred solution of2,6-dichloro-4-(2,4-difluorophenyl)nicotinaldehyde (Intermediate 2-1,500 mg, 1.7 mmol) in THF (30 mL) was added ethyl2-oxo-3-(triphenylphosphoranylidene)propanoate (653 mg, 1.7 mmol) at 15°C., then the solution was stirred at 80° C. for 24 h. The reaction wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography (ISCO®; 24 g SepaFlash® Column, eluting with 0to 5% ethyl acetate/petroleum ether) to afford the product. MS (ESI)calcd for (C₁₇H₁₂Cl₂F₂NO₃) [M+H]⁺, 386.0, found, 385.9. ¹H NMR (400 MHz,CDCl₃) δ 7.72 (d, J=16.4 Hz, 1H), 7.25-7.19 (m, 2H), 7.02 (t, J=7.2 Hz,1H), 6.96-6.87 (m, 1H), 6.82 (d, J=16.4 Hz, 1H), 4.34-4.25 (m, 2H), 1.33(t, J=7.2 Hz, 3H)

Step 2: ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-hydroxybutanoate(Intermediate 2-3)

To a solution of (E)-ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-oxobut-3-enoateobtained from Step 1 (1.1 g, 2.85 mmol) in ethanol (20 mL) was addedNaBH₄ (0.11 g, 2.85 mmol) at 20° C. and the mixture was stirred at 20°C. for 25 min. The reaction was quenched with water (250 mL) andextracted with ethyl acetate (2×200 mL), the combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography (ISCO®;24 g SepaFlash® Column, eluting with 5-15% ethyl acetate/petroleumether) to afford the product. MS (ESI) calcd for (C₁₇H₁₆Cl₂F₂NO₃)[M+H]⁺, 390.0, found, 389.9. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.13 (m,1H), 7.11 (s, 1H), 7.04-6.88 (m, 2H), 4.28-3.98 (m, 3H), 2.79-2.54 (m,2H), 1.99-1.69 (m, 2H), 1.24 (t, J=7.2 Hz, 3H)

Step 3: ethyl7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxylate

A mixture of ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-hydroxybutanoate(Intermediate 2-3, 450 mg, 1.2 mmol) and Cs₂CO₃ (751 mg, 2.3 mmol) inacetonitrile (20 mL) was stirred at 90° C. for 2.5 h. The mixture wasdiluted in water (100 mL) and extracted with ethyl acetate (2×100 mL),the combined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure and purified by silicagel chromatography (ISCO®; 12 g SepaFlash® Column, eluting with 0 to 20%ethyl acetate/petroleum ether at 30 mL/min) to afford the product. ¹HNMR (400 MHz, CDCl₃) δ 7.23-7.14 (m, 1H), 7.02-6.87 (m, 2H), 6.86 (s,1H), 4.96 (t, J=4.9 Hz, 1H), 4.25 (qq, J=7.2, 10.8 Hz, 2H), 2.50 (br.s., 2H), 2.25-2.10 (m, 2H), 1.33-1.17 (m, 3H.)

Step 4:(7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methanol

A stirred solution of ethyl7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxylate(300 mg, 0.85 mmol) in ethanol (6 mL) was added NaBH₄ (32 mg, 0.85 mmol)at 20° C., and the mixture was stirred at 20° C. for 1.5 h. NaBH₄ (32mg, 0.85 mmol) was added, and the mixture was stirred at 20° C. for 2 h.Acetone (1 mL) was added to quench the reaction, then the mixture wasdissolved in water (60 mL) and extracted with ethyl acetate (2×60 mL),the combined organics were dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (ISCO®; 4 g SepaFlash® Column, eluting with 30 to 70%ethyl acetate/petroleum ether) to afford the product. MS (ESI) calcd for(C₁₅H₁₃ClF₂NO₂) [M+H]⁺, 312.0, found, 311.9. ¹H NMR (400 MHz, CDCl₃) δ7.25-7.17 (m, 1H), 7.03-6.90 (m, 2H), 6.86 (s, 1H), 4.46-4.29 (m, 1H),4.01-3.85 (m, 1H), 3.85-3.69 (m, 1H), 2.68 (d, J=11.7 Hz, 1H), 2.54-2.43(m, 1H), 2.16 (t, J=6.8 Hz, 1H), 2.00-1.91 (m, 1H), 1.89-1.75 (m, 1H)

Step 5: ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(Intermediate 2-4)

To a stirred solution of(7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methanol(160 mg, 0.51 mmol) in ethanol (20 mL) was added PdCl₂(dppf) (38 mg,0.05 mmol) and potassium acetate (101 mg, 1.0 mmol) at 80° C. under N₂atmosphere. The mixture was degassed and backfilled with CO (threetimes). The resulting mixture was stirred under 50 psi of CO at 80° C.for 20 h. The mixture was concentrated under reduced pressure, theresidue was purified by silica gel chromatography (ISCO®; 4 g SepaFlash®Column, eluting with 30 to 80% ethyl acetate/petroleum ether) to affordthe product. MS (ESI) calcd for (C₁₈H₁₈F₂NO₄) [M+H]⁺, 350.1, found,350.1. ¹H NMR (400 MHz, CDCl₃) δ 7.66 (s, 1H), 7.25-7.20 (m, 1H),7.10-6.89 (m, 2H), 4.53-4.32 (m, 3H), 4.00-3.90 (m, 1H), 3.86-3.74 (m,1H), 2.60 (d, J=17.2 Hz, 1H), 2.25 (t, J=6.6 Hz, 1H), 2.02-1.80 (m, 2H),1.41 (t, J=7.2 Hz, 3H)

Step 6: ethyl(S)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

Racemic ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]-pyridine-7-carboxylate(60 mg, 0.17 mmol) was separated by chiral SFC (Column: Chiralpak Whelk250×30 mm, 10 um; Mobile phase: 40% to 40% MeOH (containing 0.05% DEA)in CO₂; Flow rate: 60 mL/min) to afford the two enantiomers.

Step 7:(S)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one enantiomer of ethyl(S)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(25 mg, 0.07 mmol) in ammonia (10M in MeOH) (10 mL) and stirred at 26°C. for 12 h. The mixture was concentrated under reduced pressure and theresidue was purified by prep-TLC (silica gel, eluting with 4:1 ethylacetate/petroleum ether) to afford one enantiomer of the title compound.MS (ESI) calcd. for (C₁₆H₁₅F₂N₂O₃) [M+H]⁺, [321.1], found, [321.0]. ¹HNMR (400 MHz, CDCl₃) δ 7.55 (s, 1H), 7.40-7.35 (m, 1H), 7.14-7.08 (m,2H), 4.59-4.32 (m, 1H), 3.79-3.77 (m, 2H), 2.83-2.75 (m, 1H), 2.59-2.55(m, 1H), 2.06-2.02 (m, 1H), 1.75-1.73 (m, 1H).

Similar treatment of the other enantiomer of ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other enantiomer of the title compound. MS (ESI) calcd. for(C₁₆H₁₅F₂N₂O₃) [M+H]⁺, [321.1], found, [321.0]. ¹H NMR (400 MHz, CDCl₃)δ 7.56 (s, 1H), 7.42-7.38 (m, 1H), 7.15-7.12 (m, 2H), 4.36-4.34 (m, 1H),3.8 (s, 2H), 2.84-2.76 (m, 1H), 2.60-2.56 (m, 1H), 2.07-2.03 (m, 1H),1.80-1.75 (m, 1H).

Example 2-2A, 2-2B, 2-2C and 2-2D

(2S,3R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide,(2S,3S)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide,(2R,3R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide,(2R,3S)-5-(2,4-difluorophenyl)-2-(hydroxmethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-oxobutanoate

A solution of (E)-ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-oxobut-3-enoate(Intermediate 2-2, 1.6 g, 4.14 mmol) andtris(triphenylphosphine)rhodium(I) chloride (0.77 g, 0.83 mmol) in THF(20 mL) and t-BuOH (20.00 mL) was stirred at 35° C. under 50 psi H₂ for1.5 h. The solution was concentrated in vacuo, the residue was purifiedby silica gel chromatography (ISCO®; 24 g SepaFlash® Column, elutingwith [0-5]% ethyl acetate/petroleum ether at 35 mL/min) to afford theproduct. MS (ESI) calcd. for (C₁₇H₁₄Cl₂F₂NO₃) [M+H]⁺, 389.1, found,387.7. ¹H NMR (400 MHz, CDCl₃) δ 7.05-7.22 (m, 2H), 6.84-6.99 (m, 2H),4.22 (q, J=7.04 Hz, 2H), 2.94-3.05 (m, 2H), 2.83 (d, J=7.43 Hz, 2H),1.24-1.33 (m, 3H).

Step 2: ethyl3-((2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)methyl)-2-oxobut-3-enoate

To a solution of ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-oxobutanoate (3 g,7.73 mmol) and N-methylanilinium trifluoroacetate (6.84 g, 31 mmol) inTHF (70 mL) was added paraformaldehyde (234 mg, 7.7 mmol), then themixture was stirred at 70° C. under N₂ for 14 h. The reaction wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with 50:1 to 10:1 petroleum ether:ethylacetate) to give the product. MS (ESI) calcd. for (C₁₈H₁₄Cl₂F₂NO₃)[M+H]⁺, 400.2, found: 399.9. ¹H NMR (400 MHz, CDCl₃) δ 7.21 (s, 1H),7.09-7.17 (m, 1H), 6.88-7.00 (m, 2H), 6.21 (s, 1H), 5.73 (s, 1H), 4.34(q, J=7.06 Hz, 2H), 3.62 (br. s., 2H), 1.36 (t, J=7.06 Hz, 3H).

Step 3: ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-3-methyl-2-oxobutanoate

A solution of ethyl3-((2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)methyl)-2-oxobut-3-enoate(750 mg, 1.87 mmol) and tris(triphenylphosphine)rhodium(I) chloride (347mg, 0.38 mmol) in THF (15 mL) and t-BuOH (15.00 mL) was stirred at 40°C. under 50 psi H₂ for 2 h. The solution was concentrated in vacuo, theresidue was purified by silica gel chromatography (ISCO®; 4 g SepaFlash®Column, eluting with 0% to 5% ethyl acetate/petroleum ether) to affordthe product. MS (ESI) calcd. for (C₁₈H₁₆Cl₂F₂NO₃) [M+H]⁺, 402.1, found,401.9. ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.17 (m, 1H), 7.07 (s, 1H),6.86-6.98 (m, 2H), 4.13-4.20 (m, 2H), 2.37-3.20 (m, 3H), 1.13-1.32 (m,6H)

Step 4: ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-hydroxy-3-methylbutanoate

To a solution of ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-3-methyl-2-oxobutanoate(470 mg, 1.169 mmol) in EtOH (15 mL) was added NaBH₄ (30 mg, 0.79 mmol)at 0° C. under N₂. The reaction mixture was stirred for 0.5 h. Then themixture was poured into 15 mL saturated aqueous NH₄Cl. The aqueous layerwas extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine (sat. 10 mL), dried over anhydrous Na₂SO₄, filteredand concentrated. The crude compound was purified by silica gelchromatography (ISCO®; 4 g SepaFlash® Column, eluting with 0% to 10%ethyl acetate/petroleum ether) to afford the product. MS (ESI) calcd.for (C₁₈H₁₈Cl₂F₂NO₃) [M+H]⁺, 404.0, found, 403.9. ¹H NMR (400 MHz,CDCl₃) δ 7.03-7.17 (m, 2H), 6.83-6.98 (m, 2H), 4.01-4.22 (m, 3H),2.41-2.87 (m, 3H), 1.11-1.27 (m, 6H).

Step 5: ethyl7-chloro-5-(2,4-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxylate

To a solution of ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-hydroxy-3-methylbutanoate(410 mg, 1.01 mmol) in acetonitrile (30 mL) was added Cs₂CO₃ (661 mg,2.03 mmol), the reaction mixture was stirred at 85° C. for 2 h under N₂.The mixture was filtered and the filtrate was evaporated. The crudemixture was purified by silica gel chromatography (eluting with 20:1 to5:1 petroleum ether:ethyl acetate) to give the product. MS (ESI) calcdfor (C₁₈H₁₇ClF₂NO₃) [M+H]⁺, 368.0, found, 368.0. ¹H NMR (400 MHz, CDCl₃)δ 7.11-7.23 (m, 1H), 6.83-7.02 (m, 3H), 4.59-4.86 (m, 1H), 4.13-4.32 (m,2H), 2.11-2.67 (m, 3H), 1.23-1.27 (m, 3H), 0.96-1.09 (m, 3H).

Step 6:(7-chloro-5-(2,4-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methanol

To a solution of ethyl7-chloro-5-(2,4-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxylate(310 mg, 0.84 mmol) in THF (15 mL) was added LiBH₄ (73.4 mg, 3.37 mmol)and the mixture was stirred at 20° C. under N₂ for 1 h. The mixture waspoured into 15 mL saturated aqueous NH₄Cl. The aqueous layer wasextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine (sat. 10 mL), dried over anhydrous Na₂SO₄, filtered and thefiltrate was evaporated. The crude mixture was purified by silica gelchromatography (ISCO®; 4 g SepaFlash® Column, eluting with 0% to 40%ethyl acetate/petroleum ether) to afford the product. MS (ESI) calcd.for (C₁₆H₁₅ClF₂NO₂) [M+H]⁺, 326.1, found, 325.9. ¹H NMR (400 MHz, CDCl₃)δ 7.15-7.23 (m, 1H), 6.88-7.02 (m, 2H), 6.83 (d, J=3.52 Hz, 1H),3.86-4.04 (m, 2H), 3.66-3.85 (m, 1H), 2.16-2.48 (m, 3H), 0.86-1.05 (m,3H).

Step 7: ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of(7-chloro-5-(2,4-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methanol(210 mg, 0.65 mmol), potassium acetate (190 mg, 1.93 mmol) in dry EtOH(50 mL) was added Pd(dppf)Cl₂ (70.8 mg, 0.10 mmol) under an atmosphereof CO. The reaction mixture was stirred at 70° C. under 50 psi CO for 14h. The solution was concentrated in vacuo, the residue was purified bysilica gel chromatography (ISCO®; 4 g SepaFlash® Column, eluting with 0%to 70% ethyl acetate/petroleum ether) to afford the product. MS (ESI)calcd. for (C₁₉H₂₀F₂NO₄) [M+H]⁺, 364.1, found, 364.3. ¹H NMR (400 MHz,CDCl₃) δ 7.66 (d, J=2.65 Hz, 1H), 7.19-7.25 (m, 1H), 6.87-7.06 (m, 2H),4.45 (q, J=7.06 Hz, 2H), 3.92-4.15 (m, 2H), 3.69-3.88 (m, 1H), 2.20-2.63(m, 2H), 2.05-2.14 (m, 1H), 1.41 (t, J=7.06 Hz, 3H), 0.88-1.09 (m, 3H).

Step 8: ethyl(2S,3R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate,ethyl(2S,3S)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate,ethyl(2R,3R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(2R,3S)-5-(2,4-difluorophenyl)-2-(hydroxmethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(Intermediates 2-5A, 2-5B, 2-5C, 2-5D)

Diastereomeric ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(30 mg, 0.083 mmol) was resolved by chiral SFC (Column: ChiralpakWhelk-01 250×30 mm, 10 um; Mobile phase: 40% to 40% MeOH (containing0.05% DEA) in CO₂; Flow rate: 60 mL/min) to give the four isomers of thetitle compounds.

Step 9:(2S,3R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide,(2S,3S)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide,(2R,3R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide,(2R,3S)-5-(2,4-difluoropheny)-2-(hydroxmethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one resolved isomer of ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(8 mg, 0.028 mmol) in ammonia (10 M in MeOH) (10 mL) was stirred at roomtemperature for 10 h. The mixture was concentrated and the residue waspurified by Prep-HPLC (Column: Phenomenex Synergi C18 150×30 mm, 4 um;Mobile phase: 42% to 62% water (containing 0.1% TFA)-ACN; Flow rate: 25mL/min) to give one isomer of the title compound. MS (ESI) calcd. for(C₁₇H₁₇F₂N₂O₃) [M+H]⁺, 335.0, found, 334.9. ¹H NMR (400 MHz, CD₃OD) δ7.57 (s, 1H), 7.29-7.45 (m, 1H), 7.02-7.19 (m, 2H), 4.00-4.09 (m, 1H),3.90-3.99 (m, 1H), 3.77-3.89 (m, 1H), 2.53-2.67 (m, 1H), 2.40-2.52 (m,1H), 2.05 (d, J=16.32 Hz, 1H), 1.05 (d, J=6.39 Hz, 3H).

Similar treatment of the other isomers of ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other isomers of the title compound.

Isomer 2: MS (ESI) calcd. for (C₁₇H₁₇F₂N₂O₃) [M+H]⁺, 335.0, found,334.9. ¹H NMR (400 MHz, CD₃OD) δ 7.65-7.82 (m, 2H), 7.18-7.24 (m, 1H),6.86-7.08 (m, 2H), 5.98-6.18 (m, 1H), 4.47 (br. s., 1H), 3.92-4.05 (m,1H), 3.77-3.88 (m, 1H), 2.76-2.94 (m, 1H), 2.19-2.42 (m, 2H), 0.94 (d,J=6.39 Hz, 3H).

Isomer 3: MS (ESI) calcd. for (C₁₇H₁₇F₂N₂O₃) [M+H]⁺, 335.0, found,334.9. ¹H NMR (400 MHz, CD₃OD) δ 7.55 (s, 1H), 7.29-7.44 (m, 1H),6.99-7.21 (m, 2H), 3.98-4.07 (m, 1H), 3.89-3.97 (m, 1H), 3.77-3.87 (m,1H), 2.51-2.63 (m, 1H), 2.38-2.50 (m, 1H), 1.97-2.13 (m, 1H), 1.03 (d,J=6.65 Hz, 3H).

Isomer 4: MS (ESI) calcd. for (C₁₇H₁₇F₂N₂O₃) [M+H]⁺, 335.0, found,334.9. ¹H NMR (400 MHz, CDCl₃) δ 7.67 (br. s., 2H), 7.13-7.18 (m, 1H),6.78-6.99 (m, 2H), 5.82 (br. s., 1H), 4.41 (br. s., 1H), 3.86-4.08 (m,1H), 3.75 (d, J=9.00 Hz, 1H), 2.68-2.96 (m, 1H), 2.15-2.40 (m, 2H), 0.87(d, J=5.87 Hz, 3H).

Example 2-3A and 2-3B

2-3A:(R)-2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand 2-3B:(S)-2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: (E)-methyl 3-(4-bromo-2,6-dichloropyridin-3-yl)acrylate

A solution of 4-bromo-2,6-dichloronicotinaldehyde (6 g, 23.8 mmol) andmethyl 2-(triphenylphosphoranylidene)acetate (9.5 g, 30 mmol) in THF(150 mL) was stirred at 80° C. under N₂ for 2 h. The solvent was removedunder reduced pressure, the residue was purified by silica gelchromatography (eluting with 20:1 petroleum ether/ethyl acetate) to givethe product.

Step 2: (E)-methyl3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)acrylate

A mixture of (E)-methyl 3-(4-bromo-2,6-dichloropyridin-3-yl)acrylate(6.5 g, 21 mmol), (2,4-difluorophenyl)boronic acid (3.3 g, 21 mmol),Pd(dppf)Cl₂ (1.5 g, 2.1 mmol) and NaHCO₃ (3.5 g, 42 mmol) in1,4-dioxane/water (50 mL/10 mL) was stirred at 100° C. under N₂ for 3 h.The mixture was concentrated in vacuo. The residue was purified bysilica gel chromatography (20:1 petroleum ether/ethyl acetate to givethe product. MS (ESI) calcd. for (C₁₅H₁₀Cl₂F₂NO₂) [M+H]⁺, 344.0, found,344.2. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J=16 Hz, 1H), 6.96-7.20 (m,2H), 6.86-6.92 (m, 2H), 5.90 (m, 1H), 3.71 (s, 3H).

Step 3: methyl3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propanoate(Intermediate 2-6)

A solution of Rh(PPh₃)Cl₂ (1.35 g, 1.46 mmol) and (E)-methyl3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)acrylate (2.5 g, 7.3mmol) in THF/t-BuOH (20 mL/20 mL) was stirred at 40° C. under 50 psi H₂for 12 h. MeOH was removed under reduced pressure and the crude residuewas purified by silica gel chromatography (5:1 petroleum ether/ethylacetate) to give the product. MS (ESI) calcd. for (C₁₅H₁₂Cl₂F₂NO₂)[M+H]⁺, 346.0, found, 346.1. ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.17 (m,2H), 6.92-7.01 (m, 2H), 3.58 (s, 3H), 2.86-2.90 (m, 2H), 2.44-2.48 (m,2H).

Step 4: 3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propan-1-ol

To the solution of methyl3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propanoate (850 mg,2.5 mmol) in THF (15 mL) was added LiBH₄ (68.2 mg, 9.82 mmol) at 0° C.under N₂. The resulting mixture was stirred at 18° C. for 16 h. Thereaction was poured into water (30 mL) and extracted with ethyl acetate(30 mL×3). The combined organic layers were concentrated in vacuo andthe residue was purified by silica gel chromatography (ISCO®; 4 gSepaFlash® Column, eluting with 0-30% ethyl acetate/petroleum ether) togive the product. MS (ESI) calcd. for (C₁₄H₁₂Cl₂F₂NO) [M+H]⁺, 318.0,found, 318.1. ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.22 (m, 1H), 7.12 (s, 1H),6.91-7.03 (m, 2H), 3.49-3.55 (m, 2H), 2.66 (br. s., 2H), 1.68 (br. s.,2H).

Step 5: 3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propanal(Intermediate 2-7)

To a solution of3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propan-1-ol (525 mg,1.65 mmol) in DCM (10 mL) was added DMP (840 mg, 1.980 mmol) at 0° C.and the reaction was stirred at 0° C. for 1 h. The mixture wasconcentrated in vacuo and the residue was purified by silica gelchromatography (ISCO®; 12 g SepaFlash® Column, eluting with 15% ethylacetate/petroleum ether) to give the product. MS (ESI) calcd. for(C₁₄H₁₀Cl₂F₂NO) [M+H]⁺, 316.0, found, 315.9.

Step 6:1-cyclopropyl-3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propan-1-ol

To a solution of3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propanal (350 mg, 1.1mmol) in THF (15 mL) at 0° C. was added cyclopropylmagnesium bromide(4.4 mL, 2.2 mmol). The mixture was stirred at 0° C. for 1 h. Thereaction was poured into saturated aqueous NH₄Cl solution (30 mL). Themixture was extracted with ethyl acetate (20 mL×3), the combined organiclayers were washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (ISCO®; 12 g SepaFlash® Column, eluting with 15% ethylacetate/petroleum ether) to give the product. MS (ESI) calcd. for(C₁₇H₁₆Cl₂F₂NO) [M+H]⁺, 358.1, found, 357.9. ¹H NMR (400 MHz, CDCl₃) δ7.07-7.15 (m, 1H), 7.04 (s, 1H), 6.83-6.95 (m, 2H), 3.40 (s, 2H),2.60-2.69 (m, 2H), 1.52 (br. s., 1H), 0.66 (dd, J=4.41, 8.16 Hz, 1H),0.35 (d, J=7.94 Hz, 2H), 0.07-0.15 (m, 1H), −0.02-0.06 (m, 1H).

Step 7:7-chloro-2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine

A mixture of1-cyclopropyl-3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propan-1-ol (250 mg, 0.698 mmol) and Cs₂CO₃ (568 mg, 1.745 mmol) in MeCN(10 mL) was stirred at 90° C. for 16 h. The mixture was concentrated invacuo and the residue was purified by silica gel chromatography (ISCO®;12 g SepaFlash® Column, eluting with 15% ethyl acetate/petroleum ether)to give the product. MS (ESI) calcd. for (C₁₇H₁₅ClF₂NO) [M+H]⁺, 322.0,found, 321.9.

Step 5: Ethyl2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

A mixture of7-chloro-2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine(180 mg, 0.56 mmol), potassium acetate (110 mg, 1.1 mmol) andPdCl₂(dppf) (82 mg, 0.11 mmol) in EtOH (15 mL) was stirred at 80° C.under 50 Psi of CO for 5 h. The mixture was concentrated in vacuo andthe residue was purified by silica gel chromatography (ISCO®; 4 gSepaFlash® Column, eluting with 20% ethyl acetate/petroleum ether) togive the product. MS (ESI) calcd. for (C₂₀H₁₉F₂NO₃Na) [M+Na]⁺, 382.1,found, 382.0.

Step 8: ethyl(S)-2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(R)-2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

Racemic ethyl2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(160 mg, 0.45 mmol) was resolved by chiral SFC (Column: Chiralpak AD250×30 mm, 5 um; Mobile phase: 40% to 40% EtOH (containing 0.05% DEA) inCO₂; Flow rate: 65 mL/min) to give the two enantiomers.

Step 9:(S)-2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one enantiomer of ethyl2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(70 mg, 0.20 mmol) in ammonia (10 M in MeOH) (15 mL) was stirred at 19°C. for 5 h. The reaction was concentrated in vacuo and the residue waspurified by Prep-HPLC (Column: Phenomenex Synergi C18 150×30 mm, 4 um;Mobile phase: 50% to 70% water (containing 0.1% TFA)-ACN; Flow rate: 25mL/min) to give one enantiomer of the title compound. MS (ESI) calcd.for (C₁₈H₁₇F₂N₂O₂) [M+H]⁺, 331.1, found, 331.0. ¹H NMR (400 MHz, CD₃OD)δ 7.18 (s, 1H), 6.96-7.06 (m, 1H), 6.69-6.80 (m, 2H), 3.28 (t, J=8.27Hz, 1H), 2.31-2.43 (m, 1H), 2.17-2.28 (m, 1H), 1.79 (d, J=13.67 Hz, 1H),1.38-1.51 (m, 1H), 0.72-0.84 (m, 1H), 0.13-0.34 (m, 3H), −0.01-0.08 (m,1H).

Similar treatment of the other enantiomer of ethyl2-cyclopropyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other enantiomer of the title compound. ¹H NMR (400 MHz,CD₃OD) δ 7.19 (s, 1H), 6.96-7.05 (m, 1H), 6.70-6.79 (m, 2H), 3.28 (t,J=8.38 Hz, 1H), 2.31-2.44 (m, 1H), 2.15-2.28 (m, 1H), 1.79 (d, J=13.89Hz, 1H), 1.37-1.51 (m, 1H), 0.72-0.83 (m, 1H), 0.13-0.34 (m, 3H),−0.02-0.07 (m, 1H).

Example 2-4A and 2-4B

(S)-5-(2,4-difluorophenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: (E)-ethyl3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)acrylate

A solution of 2,6-dichloro-4-(2,4-difluorophenyl)nicotinaldehyde (6 g,21 mmol) and ethyl 2-(triphenylphosphoranylidene)acetate (8.7 g, 25mmol) in THF (100 mL) was stirred at 70° C. for 12 h. The solvent wasremoved under reduced pressure. The residue was purified by silica gelchromatography (10:1 petroleum ether/ethyl acetate) to give the product.MS (ESI) calcd. for (C₁₆H₁₂Cl₂F₂NO₂) [M+H]⁺, 358.0, found, 358.2.

Step 2: ethyl3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propanoate

A solution of Rh(PPh₃)Cl₂ (5.8 g, 6.3 mmol) and (E)-ethyl3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)acrylate (7.5 g, 21.0mmol) in THF/t-BuOH (50 mL/50 mL) was stirred at 50° C. under 40 psi H₂for 12 h. MeOH was removed under reduced pressure and the residue waspurified by silica gel chromatography (10:1 petroleum ether/ethylacetate) to give the product. MS (ESI) calcd. for (C₁₆H₁₄Cl₂F₂NO₂)[M+H]⁺, 360.0, found, 360.2. ¹H NMR (400 MHz, CD₃OD) δ 7.32-7.38 (m,2H), 7.18-7.10 (m, 2H), 4.01 (t, J=6.4 Hz, 2H), 2.89 (m, 2H), 2.43 (t,J=8.4 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H).

Step 3: 3-(2,6-dichloro-4-(2,4-difluoropheny)pyridin-3-yl)propanoic acid

Ethyl 3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propanoate (0.6g, 1.7 mmol) was dissolved in (40 mL) (THF:H₂O=3:1). The mixture wasstirred at 25° C. Then LiOH (0.21 g, 5.1 mmol) was added to thesolution. The mixture was stirred at 25° C. for 4 h. The mixture wasconcentrated under reduce pressure and adjusted to pH 5 with citric acidmonohydrate. The mixture was extracted with ethyl acetate (20 mL×3) anddried over anhydrous Na₂SO₄. The combined organic layers wereconcentrated to afford the product which was used in the next stepwithout further purification. MS (ESI) calcd for (C₁₄H₁₀Cl₂F₂NO₂)[M+H]⁺, 332.0, found, 331.9.

Step 4:3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-N-methoxy-N-methylpropanamide

To a solution of3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propanoic acid (0.5g, 1.5 mmol) in THF (15 mL) was added HATU (0.76 g, 2 mmol) followed byTEA (0.45 g, 4.5 mmol). The mixture was stirred at 25° C. for 10 min.Then N,O-dimethylhydroxylamine hydrochloride (0.2 g, 2.0 mmol) was addedto the mixture. The reaction was stirred at 25° C. for 1 h. The mixturewas concentrated under reduce pressure and the residue was purified bysilica gel chromatography (ISCO®; 4 g SepaFlash® Column, eluting with 0%to 20% ethyl acetate/petroleum ether) to give the product. MS (ESI)calcd for (C₁₆H₁₅Cl₂F₂N₂O₂) [M+H]⁺, 375.0, found, 374.9.

Step 5:1-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-4-methylpentan-3-one

To a solution of3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-N-methoxy-N-methylpropanamide(0.5 g, 1.3 mmol) in THF (20 mL) at 0° C. under N₂ was addedisopropylmagnesium chloride (1.3 mL) dropwise. The mixture was stirredat 25° C. for 6 h. The mixture was concentrated under reduced pressureand poured into water (50 mL) and extracted with ethyl acetate (30mL×3). The combined organic phases were washed with HCl (1 M, 2×20 mL)and brine (20 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography (elutingwith ethyl acetate/petroleum ether) to afford the product. MS (ESI)calcd for (C₁₇H₁₆Cl₂F₂NO) [M+H]⁺, 358.0, found, 357.9.

Step 6:1-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-4-methylpentan-3-ol

To a solution of1-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-4-methylpentan-3-one(0.14 g, 0.39 mmol) in CH₃OH (10 mL) at 0° C. under N₂ was added NaBH₄(0.015 g, 0.4 mmol). The mixture was stirred at 0° C. for 0.5 h. Themixture was poured into water (10 mL) and extracted with ethyl acetate(20 mL×3). The combined organic layers were concentrated under reducepressure. The residue was purified by Prep-TLC (silica gel, eluting with1:10 ethyl acetate/petroleum ether) to afford the product. MS (ESI)calcd for (C₁₇H₁₈Cl₂F₂NO) [M+H]⁺, 360.1, found, 359.9.

Step 7:7-chloro-5-(2,4-dimethylphenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine

To a solution of1-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-4-methylpentan-3-olin CH₃CN (20 mL) was added Cs₂CO₃ (0.2 g, 0.6 mmol) and the mixture wasstirred at 90° C. for 10 h. The solution was poured into H₂O (20 mL) andextracted with ethyl acetate (20 mL×3). The combined organic layers wereconcentrated under reduce pressure and purified by Prep-TLC (silica gel,eluting with 1:10 ethyl acetate/petroleum ether) to afford the product.¹H NMR (400 MHz, CDCl₃) δ 7.18-7.07 (m, 1H), 6.96-6.80 (m, 2H), 6.72 (s,1H), 3.98-3.85 (m, 1H), 2.64-2.46 (m, 1H), 2.42-2.30 (m, 1H), 2.00-1.81(m, 2H), 1.66-1.47 (m, 1H), 1.05-0.90 (m, 6H)

Step 8: ethyl5-(2,4-difluorophenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of7-chloro-5-(2,4-dimethylphenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine(0.1 g, 0.29 mmol) in EtOH (15 mL) was added Pd(dppf)Cl₂ (0.021 g, 0.029mmol) and KOAc (0.058 g, 0.58 mmol). The mixture was stirred at 60° C.under an atmosphere of CO for 10 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified byPrep-TLC (silica gel, eluting with 1:4 ethyl acetate/petroleum ether) toafford the product. MS (ESI) calcd for (C₂₀H₂₂F₂NO₃) [M+H]⁺, 362.0,found, 361.9. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (s, 1H), 7.27-7.13 (m, 1H),7.03-6.82 (m, 2H), 4.40 (q, J=7.3 Hz, 2H), 3.98 (dd, J=5.7, 9.2 Hz, 1H),2.79-2.44 (m, 2H), 2.11-1.82 (m, 3H), 1.72-1.54 (m, 1H), 1.37 (t, J=7.0Hz, 3H), 1.11-0.93 (m, 6H).

Step 9: ethyl(S)-5-(2,4-difluorophenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(R)-5-(2,4-difluorophenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

Racemic ethyl5-(2,4-difluorophenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(90 mg, 0.25 mmol) was resolved by chiral SFC (Column: Chiralpak AD250×30 mm, 5 um; Mobile phase: 40% to 40% EtOH (containing 0.05% DEA) inCO₂; Flow rate: 65 mL/min) to give the two enantiomers.

Step 10(S)-5-(2,4-difluorophenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand ethyl(R)-5-(2,4-difluorophenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

A solution of one enantiomer of ethyl5-(2,4-difluorophenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(40 mg, 0.11 mmol) in ammonia (10 M in MeOH) (20 mL) was stirred at 20°C. for 16 h. The mixture was concentrated under reduced pressure. Theresidue was purified by Prep-TLC to give one enantiomer of the titlecompound. MS (ESI) calcd. for (C₁₈H₁₉F₂N₂O₂) [M+H]⁺, 333.1, found,332.9. ¹H NMR (400 MHz, CD₃OD) δ 7.46 (br. s., 1H), 7.35-7.24 (m, 1H),7.09-6.97 (m, 2H), 3.96 (dd, J=5.6, 9.2 Hz, 1H), 2.76-2.60 (m, 1H),2.54-2.39 (m, 1H), 2.00-1.82 (m, 2H), 1.67-1.47 (m, 1H), 0.99 (dd,J=6.8, 16.8 Hz, 6H)

Similar treatment of the other enantiomer of ethyl5-(2,4-difluorophenyl)-2-isopropyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other enantiomer of the title compound. MS (ESI) calcd. for(C₁₈H₁₉F₂N₂O₂) [M+H]⁺, 333.1, found, 332.9. ¹H NMR (400 MHz, CD₃OD) δ7.56 (br. s., 1H), 7.43-7.34 (m, 1H), 7.18-7.06 (m, 2H), 4.05 (dd,J=5.4, 9.4 Hz, 1H), 2.87-2.68 (m, 1H), 2.64-2.49 (m, 1H), 2.13-1.91 (m,2H), 1.77-1.59 (m, 1H), 1.09 (dd, J=6.7, 16.6 Hz, 6H).

Example 2-5

5-(2,4-difluorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1:4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-methylbutan-2-ol

Methylmagnesium bromide (0.64 mL, 1.9 mmol) was added dropwise to asolution of methyl3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propanoate(Intermediate 2-6, 110 mg, 0.32 mmol) in THF (3 mL) at 0° C. under anatmosphere of N₂. The resulting mixture was stirred at 0° C. for 1 h.The mixture was quenched with saturated aqueous NH₄Cl (20 mL). Then themixture was extracted with ethyl acetate (10 mL×3). The mixture wasconcentrated in vacuo and the residue was purified by Prep-TLC (silicagel, eluting with 1:3 ethyl acetate/petroleum ether) to give theproduct. MS (ESI) calcd. for (C₁₆H₁₆Cl₂F₂NO) [M+H]⁺, 346.0, found,345.9. ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.14 (m, 1H), 7.11 (s, 1H),7.04-6.91 (m, 2H), 2.64 (br. s., 2H), 1.53 (d, J=3.9 Hz, 2H), 1.09 (s,6H).

Step 2:7-chloro-5-(2,4-difluorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine

A mixture of4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-methylbutan-2-ol(65 mg, 0.19 mmol) and Cs₂CO₃ (120 mg, 0.38 mmol) in DMA (5 mL) wasstirred at 120° C. for 19 h. The reaction mixture was washed with water(10 mL) and extracted with ethyl acetate (5 mL×3). The combined organiclayers were concentrated in vacuo to give crude product, which waspurified by Prep-TLC (silica gel, eluting with 1:3 ethylacetate/petroleum ether) to give the product. MS (ESI) calcd. for(C₁₆H₁₅ClF₂NO) [M+H]⁺, 310.1, found, 310.1.

Step 3: ethyl5-(2,4-difluorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of7-chloro-5-(2,4-difluorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine(25 mg, 0.08 mmol) and potassium acetate (15.8 mg, 0.16 mmol) in EtOH(10 mL) was added PdCl₂(dppf) (11.8 mg, 0.016 mmol) under N₂ atmosphere.The mixture was degassed and backfilled with CO (three times). Theresulting mixture was stirred under 50 psi of CO at 80° C. for 30 h. Thecatalyst was filtered off and filtrate was concentrated under reducedpressure and purified by Prep-TLC (silica gel, eluting with 1:5 ethylacetate/petroleum ether) to give the product. MS (ESI) calcd. for(C₁₉H₂₀F₂NO₃) [M+H]⁺, 348.1, found, 348.5.

Step 4:5-(2,4-difluorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of5-(2,4-difluorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(15 mg, 0.05 mmol) in NH₃/MeOH (20 mL) was stirred at 25° C. for 24 h.The mixture was concentrated under reduced pressure and purified byPrep-TLC (silica gel, ethyl acetate) to give the title compound. MS(ESI) calcd. for (C₁₇H₁₇F₂N₂O₂) [M+H]⁺, 319.1, found, 318.9. ¹H NMR (400MHz, CD₃OD) δ 7.55 (s, 1H), 7.45-7.35 (m, 1H), 7.19-7.07 (m, 1H), 2.66(t, J=6.5 Hz, 2H), 1.84 (t, J=6.7 Hz, 2H), 1.43 (s, 6H).

Example 2-6A and 2-6B

(R)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(S)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: 4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)butan-2-ol

Methylmagnesium bromide (1.7 mL, 5.1 mmol) was added to the solution of3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)propanal(Intermediate 2-7, 270 mg, 0.85 mmol) in THF (10 mL) at 0° C. under N₂.The resulting mixture was stirred at 0° C. for 1.5 h. The mixture wasquenched with saturated aqueous NH₄Cl (50 mL) and extracted with ethylacetate (50 mL×3). The combined organic layers were concentrated invacuo and purified by silica gel chromatography (ISCO®; 4 g SepaFlash®Column, eluting with 0-30% ethyl acetate/petroleum ether) to give theproduct. MS (ESI) calcd. for (C₁₅H₁₄Cl₂F₂NO) [M+H]⁺, 332.0, found,331.9.

Step 2:7-chloro-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine

A mixture of4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)butan-2-ol (200 mg,0.60 mmol) and Cs₂CO₃ (392 mg, 1.20 mmol) in MeCN (10 mL) was stirred at90° C. for 22 h. The reaction mixture was poured into water (50 mL) andextracted with ethyl acetate (30 mL×3). The combined organic layers wereconcentrated in vacuo and purified by Prep-TLC (silica gel, eluting with1:3 ethyl acetate/petroleum ether) to give the product. MS (ESI) calcd.for (C₁₅H₁₃ClF₂NO) [M+H]⁺, 296.1, found, 296.1.

Step 3: ethyl(R)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(S)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of7-chloro-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine(120 mg, 0.41 mmol) in EtOH (10 mL) was added potassium acetate (80 mg,0.81 mmol) and PdCl₂(dppf) (30 mg, 0.04 mmol) under N₂ atmosphere. Themixture was degassed and backfilled with CO (three times). The resultingmixture was stirred under 50 psi CO at 70° C. for 7 h. The mixture wasconcentrated under reduced pressure to give the crude product, which waspurified by prep-TLC (silica gel, eluting with 5:1 petroleum ether:ethylacetate) to afford the racemic product. MS (ESI) calcd. for(C₁₈H₁₈F₂NO₃) [M+H]⁺, 334.1, found, 334.1.

Racemic ethyl5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylatewas resolved by chiral SFC (Column: Chiralpak Whelk-01 250×30 mm, 10 um;Mobile phase: 40% to 40% MeOH (containing 0.05% DEA) in CO₂; Flow rate:50 mL/min) to give the two enantiomers.

Step 4:(R)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(S)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one enantiomer of ethyl5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(35 mg, 0.11 mmol) in ammonia (10 M in MeOH) (20 mL) was stirred at 15°C. for 15 h. The mixture was concentrated in vacuo and purified byPrep-HPLC (Column: Phenomenex Synergi C18 150×30 mm, 4 um; Mobile phase:43% to 63% water (containing 0.1% TFA)-ACN; Flow rate: 25 mL/min) togive one enantiomer of the title compound. MS (ESI) calcd. for(C₁₆H₁₅F₂N₂O₂) [M+H]⁺, 305.1, found, 305.0. ¹H NMR (400 MHz, CDCl₃) δ7.79-7.66 (m, 2H), 7.27-7.20 (m, 1H), 7.03-6.88 (m, 2H), 5.81 (br. s.,1H), 4.50-4.38 (m, 1H), 2.75 (br. s., 1H), 2.56 (d, J=16.5 Hz, 1H),2.07-1.97 (m, 1H), 1.76-1.59 (m, 1H), 1.52 (d, J=6.2 Hz, 3H).

Similar treatment of the other enantiomer of ethyl5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other enantiomer of the title compound. MS (ESI) calcd. for(C₁₆H₁₅F₂N₂O₂) [M+H]⁺, 305.1, found, 305.0. ¹H NMR (400 MHz, CDCl₃) δ7.72 (s, 2H), 7.26-7.20 (m, 1H), 7.03-6.88 (m, 2H), 5.66 (br. s., 1H),4.50-4.39 (m, 1H), 2.73 (br. s., 1H), 2.62-2.50 (m, 1H), 2.07-1.97 (m,1H), 1.76-1.62 (m, 1H), 1.52 (d, J=6.2 Hz, 3H).

Example 2-7

5-(2,4-difluorophenyl)-3,3-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: methyl3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-3-hydroxy-2,2-dimethylpropanoate

To a solution of methyl isobutyrate (1.7 g, 17 mmol) in THF (20 mL)under N₂ at −60° C. was added LDA (8.35 mL, 16.7 mmol). The reaction wasstirred at −60° C. for 0.5 h.2,6-dichloro-4-(2,4-difluorophenyl)nicotinaldehyde (Intermediate 2-1, 4g, 14 mmol) was added to slowly over 30 min. The reaction was stirred at−60° C. for 1 h. The mixture was quenched with saturated aqueous NH₄Cl(20 mL) and extracted with EtOAc (50 mL). The combined organic extractswere concentrated under reduced pressure and purified by silica gelchromatography (ISCO®; 40 g SepaFlash® Column, eluting with 10%-20%ethyl acetate/petroleum ether) to give the product. MS (ESI) calcd. for(C₁₇H₁₆Cl₂F₂NO₃) [M+H]⁺, 390.0, found, 389.9. ¹H NMR (400 MHz, CD₃OD) δ7.51-7.32 (m, 1H), 7.26 (s, 1H), 7.15-6.96 (m, 2H), 3.60 (s, 3H),1.02-0.91 (m, 6H).

Step 2:1-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-3-methoxy-2,2-dimethyl-3-oxopropylethyl oxalate

A mixture of3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-3-hydroxy-2,2-dimethylpropanoate(1.2 g, 3.1 mmol), ethyl 2-chloro-2-oxoacetate (830 mg, 6.1 mmol) andpyridine (478 mg, 6.1 mmol) in DCM (20 mL) was stirred at 25° C. for 12h. The mixture was quenched with water (20 mL), extracted with EtOAc (50mL) and concentrated under reduced pressure to give the product whichwas used in subsequent steps without further purification.

Step 3: methyl3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2,2-dimethylpropanoate

To a mixture of1-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-3-methoxy-2,2-dimethyl-3-oxopropylethyl oxalate (750 mg, 1.5 mmol), and Bu₃SnH (890 mg, 3.1 mmol) intoluene (20 mL) was added AIBN (75 mg, 0.46 mmol) under N₂ atmosphere.The reaction was stirred at 80° C. for 1 h. The solvent was removedunder reduced pressure the residue was purified by Prep-TLC (silica gel,eluting with 5:1 ethyl acetate/petroleum ether) to give the product. MS(ESI) calcd. for (C₁₇H₁₆Cl₂F₂NO₂) [M+H]⁺, 374.0, found, 374.0. ¹H NMR(400 MHz, CDCl₃) δ 7.19-7.12 (m, 1H), 7.06 (s, 1H), 6.99-6.83 (m, 2H),3.48 (s, 3H), 3.27-3.12 (m, 1H), 3.05-2.89 (m, 1H), 0.88 (d, J=10.6 Hz,6H).

Step 4:3-(2,6-dichloro-4-(2,4-difluoropheny)pyridin-3-yl)-2,2-dimethylpropan-1-ol

To a solution of methyl3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2,2-dimethylpropanoate(130 mg, 0.34 mmol) in THF (4 mL) was added LiBH₄ (14.5 mg, 0.66 mmol)under N₂ atmosphere. The reaction was stirred at 60° C. for 4 h thenquenched with saturated aqueous NH₄Cl (5 mL) and extracted with EtOAc(10 mL×3). The combined organic layers were dried over Na₂SO₄, filteredand concentrated to give a residue which was purified by silica gelchromatography (eluting with 10:1 ethyl acetate/petroleum ether) to givethe product. MS (ESI) calcd. for (C₁₆H₁₆Cl₂F₂NO) [M+H]⁺, 346.0, found,345.9. ¹H NMR (400 MHz, CDCl₃) δ 7.19-7.13 (m, 1H), 7.07 (s, 1H),6.99-6.83 (m, 2H), 3.09 (br. s., 2H), 2.99-2.85 (m, 1H), 2.73 (br. s.,1H), 0.61 (br. s., 6H).

Step 5:7-chloro-5-(2,4-difluoropheny)-3,3-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine

A mixture of3-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2,2-dimethylpropan-1-ol(100 mg, 0.29 mmol) and Cs₂CO₃ (190 mg, 0.58 mmol) in CH₃CN (20 mL) wasstirred at 70° C. for 12 h. The solvent was removed under reducedpressure and the residue was purified by silica gel chromatography(eluting with 10:1 ethyl acetate/petroleum ether) to give the product.MS (ESI) calcd. for (C₁₆H₁₅ClF₂NO) [M+H]⁺, 310.0, found, 310.1. ¹H NMR(400 MHz, CDCl₃) δ 7.22-7.13 (m, 1H), 7.01-6.88 (m, 2H), 6.80 (s, 1H),3.95 (s, 2H), 2.26 (br. s., 2H), 0.96 (s, 6H).

Step 6: ethyl5-(2,4-difluorophenyl)-3,3-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of7-chloro-5-(2,4-difluorophenyl)-3,3-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine(60 mg, 0.19 mmol) in EtOH (10 mL) was added potassium acetate (98 mg,0.58 mmol) and PdCl₂(dppf) (28 mg, 0.04 mmol) under N₂ atmosphere. Themixture was degassed and backfilled with CO (three times). The resultingmixture was stirred under 50 psi CO at 70° C. for 8 h. The mixture wasconcentrated under reduced pressure and the residue was purified byPrep-TLC (silica gel, eluting with 5:1 ethyl acetate/petroleum ether) togive the product. MS (ESI) calcd. for (C₁₉H₂₀F₂NO₃) [M+H]⁺, 348.1,found, 348.0. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (s, 1H), 7.25-7.18 (m, 1H),7.05-6.90 (m, 2H), 4.43 (q, J=7.1 Hz, 2H), 4.00 (s, 2H), 1.41 (t, J=7.1Hz, 3H), 0.99 (s, 6H).

Step 7:5-(2,4-difluorophenyl)-3,3-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A mixture of ethyl5-(2,4-difluorophenyl)-3,3-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(50 mg, 0.14 mmol) and ammonia in MeOH (15 mL, 150 mmol) was stirred at25° C. for 12 h. The mixture was concentrated under reduced pressure togive the title compound. MS (ESI) calcd. for (C₁₇H₁₇F₂N₂O₂) [M+H]⁺,319.1, found, 319.1. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (s, 1H), 7.42-7.32(m, 1H), 7.19-7.08 (m, 2H), 4.04 (s, 2H), 2.43 (s, 2H), 1.93 (s, 2H),0.99 (s, 6H).

Example 2-8A and 2-8B

(S)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-oxobutanoate

To a stirred solution of ethyl(E)-4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-oxobut-3-enoate(Intermediate 2-2, 2.1 g, 5.44 mmol) in THF (20 mL) and t-BuOH (20 mL)was added tris(triphenylphosphine)rhodium(I) chloride (1.0 g, 1.1 mmol)at 25° C., the solution was stirred at 40° C. under 50 psi H₂ for 19 h.The mixture was concentrated under reduced pressure, the residue waspurified by silica gel chromatography (ISCO®; 40 g SepaFlash® Column,eluting with 0% to 3% ethyl acetate/petroleum ether) to afford theproduct. MS (ESI) calcd for (C17H14Cl2F2NO3) [M+H]⁺, 388.0, found,388.0. ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.16 (m, 1H), 7.14 (s, 1H),7.06-6.91 (m, 2H), 4.34-4.22 (m, 2H), 3.16-2.98 (m, 2H), 2.90 (d, J=6.8Hz, 2H), 1.34 (t, J=7.1 Hz, 3H)

Step 2: ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-hydroxy-2-methylbutanoate

MeMgBr (0.54 mL, 1.73 mmol) was added dropwise slowly to a solution ofethyl 4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-oxobutanoate(670 mg, 1.73 mmol) in THF (18 mL) at 0° C. under N₂ atmosphere. Themixture was stirred at 25° C. for 1 h. Saturated aqueous NH₄Cl (30 mL)was added and the aqueous phase was extracted with ethyl acetate (30mL×2).

The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (ISCO®; 12 g SepaFlash® Column, eluting with 0% to10% ethyl acetate/petroleum ether) to afford the product. MS (ESI) calcdfor (C₁₈H₁₇Cl₂F₂NO₃) [M+H]⁺, 406.2, found 405.9. ¹H NMR (400 MHz, CDCl₃)δ 7.27-7.18 (m, 1H), 7.16 (s, 1H), 7.09-6.95 (m, 2H), 4.28-4.18 (m, 1H),4.18-4.07 (m, 1H), 3.09 (s, 1H), 2.79 (dt, J=3.8, 12.9 Hz, 1H), 2.48(dt, J=4.8, 12.9 Hz, 1H), 1.95 (dt, J=4.5, 12.8 Hz, 1H), 1.81-1.68 (m,1H), 1.35 (s, 3H), 1.33-1.26 (m, 3H).

Step 3: ethyl7-chloro-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxylate

To a solution of ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-hydroxy-2-methylbutanoate(270 mg, 0.66 mmol) in DMA (5 mL), Cs₂CO₃ (429 mg, 1.32 mmol) was added.The mixture was degassed and backfilled with N₂ three times. The mixturewas stirred at 100° C. for 100 min. The solution was poured into water(25 mL) and extracted with ethyl acetate (25 mL×2). The combined organiclayers were washed with water (20 mL), dried over with anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (ISCO®; 12 g SepaFlash® Column,eluting with 0% to 10% ethyl acetate/petroleum ether) to give theproduct. MS (ESI) calcd for (C₁₈H₁₆ClF₂NO₃) [M+H]⁺, 368.0, found 367.9.¹H NMR (400 MHz, CDCl₃) δ 7.17-7.07 (m, 1H), 6.95-6.81 (m, 2H), 6.78 (s,1H), 4.25-4.07 (m, 2H), 2.95-2.83 (m, 1H), 2.46-2.25 (m, 3H), 1.64 (s,3H), 1.14 (t, J=7.3 Hz, 3H).

Step 4:(7-chloro-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methanol

To a solution of ethyl7-chloro-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxylate(166 mg, 0.45 mmol) in EtOH (5 mL) was added NaBH₄ (34.8 mg, 0.9 mmol).The mixture was stirred at 0° C. for 1.5 h under N₂. Acetone (1 mL) wasadded to the mixture, the solvent was removed under reduced pressure.The residue was purified by silica gel chromatography (ISCO®; 12 gSepaFlash® Column, eluting with 10% to 30% ethyl acetate/petroleumether) to give the product. MS (ESI) calcd for (C₁₆H₁₄ClF₂NO₂) [M+H]⁺,326.0, found 325.9. ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.19 (m, 1H),7.04-6.90 (m, 2H), 6.85 (s, 1H), 3.81-3.71 (m, 1H), 3.67-3.57 (m, 1H),2.56-2.43 (m, 1H), 2.08-1.94 (m, 1H), 1.76-1.65 (m, 1H), 1.36 (s, 3H),1.29-1.21 (m, 1H).

Step 5: ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a mixture of(7-chloro-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methanol (106 mg, 0.326 mmol) and Pd(dppf)Cl₂ (24 mg, 0.03 mmol) in EtOH(30 mL) under argon was added KOAc (63.9 mg, 0.652 mmol). The mixturewas degassed and backfilled with argon three times. The resultingmixture was stirred under 50 Psi of CO at 70° C. for 24 h. The mixturewas filtered and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel chromatography (ISCO®; 12 gSepaFlash® Column, eluting with 10% to 60% ethyl acetate/petroleumether) to give the product. MS (ESI) calcd for (C₁₉H₁₉F₂NO₄) [M+H]⁺,364.1, found 364.0.

Step 6: ethyl2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a stirred solution of ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(70 mg, 0.193 mmol) in acetonitrile (7 mL) at 25° C. under N₂ was addedcuprous iodide (7.34 mg, 0.04 mmol) and2,2-difluoro-2-(fluorosulfonyl)acetic acid (68.6 mg, 0.39 mmol). Thesolution was stirred at 50° C. for 30 min. A further portion of2,2-difluoro-2-(fluorosulfonyl)acetic acid (137 mg, 0.771 mmol) wasadded at 50° C. and the solution was stirred at 50° C. for 40 min. Thesolution was poured into saturated aqueous NaHCO₃ (40 mL) and extractedwith ethyl acetate (40 mL×2), the combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC (silica gel, eluting with 2:1 petroleumether:ethyl acetate) to give the product. MS (ESI) calcd for(C₂₀H₂₀F₄NO₄) [M+H]⁺, 414.1, found, 414.0.

Step 7: ethyl(S)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(R)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

Racemic ethyl2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(22.8 mg, 0.055 mmol) was resolved by chiral SFC (Column: Chiralpak AY250×30 mm, 10 um; Mobile phase: 10% to 10% EtOH (containing 0.05% DEA)in CO₂; Flow rate: 60 mL/min) to afford the two enantiomers.

Step 8:(S)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one enantiomer of ethyl2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(10 mg, 0.024 mmol) in ammonia (10 M in MeOH) (20 mL) was stirred at 25°C. for 18 h. The mixture was concentrated under reduced pressure and theresidue was purified by Prep-HPLC (Column: Phenomenex Synergi C18 150×30mm, 4 um; Mobile phase: 50% to 70% water (containing 0.1% TFA)-ACN; Flowrate: 25 mL/min) to afford one enantiomer of the title compound. MS(ESI) calcd for (C₁₈H₁₇F₄N₂O₃) [M+H]⁺, 385.1, found, 385.0. ¹H NMR (400MHz, CDCl₃) δ 7.90 (br. s., 1H), 7.74 (s, 1H), 7.30-7.26 (m, 1H),7.07-6.87 (m, 2H), 6.66 (br. s., 1H), 6.53-6.07 (m, 1H), 4.08-3.87 (m,2H), 2.10-1.96 (m, 1H), 1.91-1.73 (m, 1H), 1.48 (s, 3H).

Similar treatment of the other enantiomer of ethyl2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other enantiomer of the title compound. MS (ESI) calcd for(C₁₈H₁₇F₄N₂O₃) [M+H]⁺, 385.1, found, 385.0. ¹H NMR (400 MHz, CDCl₃) δ7.92 (br. s., 1H), 7.74 (s, 1H), 7.29 (br. s., 1H), 7.07-6.90 (m, 2H),6.78 (br. s., 1H), 6.59-6.02 (m, 1H), 4.08-3.86 (m, 2H), 2.10-1.96 (m,1H), 1.90-1.75 (m, 1H), 1.48 (s, 3H).

Example 2-9A, 2-9B, 2-9C and 2-9D

(S)-2-((S)-1-(difluoromethoxy)ethyl)-5-(2,4-difluoropheny)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide,(S)-2-((R)-1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide,(R)-2-((S)-1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-2-((R)-1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1:7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxylicacid (Intermediate 3-2)

To a solution of ethyl4-(2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl)-2-hydroxybutanoate(Intermediate 2-3, 1.15 g, 2.9 mmol) and Cs₂CO₃ (1.9 g, 5.8 mmol) inCH₃CN (15 mL). The mixture was stirred at 90° C. for 6 h. The mixturewas poured into water (60 mL) and extracted with EtOAc (20 mL). Theaqueous phase was adjusted to pH-4 with citric acid and extracted withEtOAc (40 mL×3). The combined organic extracts were concentrated underreduce pressure to afford the product which was used in next stepwithout purification. MS (ESI) calcd for (C₁₅H₁₁ClF₂NO₃) [M+H]⁺, 325.9found, 325.9. ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.08 (m, 2H), 7.03-6.85 (m,2H), 4.98 (dd, J=3.9, 6.7 Hz, 1H), 2.78-2.43 (m, 2H), 2.36-2.07 (m, 2H).

Step 2:7-chloro-5-(2,4-difluorophenyl)-N-methoxy-N-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxamide

A mixture of7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxylicacid (0.8 g, 2.5 mmol), N,O-dimethylhydroxylamine hydrochloride (264 mg,2.7 mmol), HATU (1.02 g, 2.7 mmol) and Et₃N (720 mg, 7.35 mmol) in DCM(15 mL) was stirred at 25° C. for 2 h. The reaction was poured intowater (20 mL) and extracted with EtOAc (50 mL×3). The combined organiclayers were dried over sodium sulfate, filtered and evaporated and theresidue was purified by silica gel chromatography (eluting with 1:1petroleum ether/ethyl acetate) to give the product. MS (ESI) calcd. for(C₁₇H₁₆ClF₂N₂O₃) [M+H]⁺, 369.0, found, 369.1.

Step 3:1-(7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)ethanone

To a solution of7-chloro-5-(2,4-difluorophenyl)-N-methoxy-N-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxamide(400 mg, 1.1 mmol) in THF (10 mL) was added dropwise MeMgBr (0.4 mL, 1.2mmol) at −65° C. under N₂ and the reaction was stirred for 2 h at −65°C. The reaction was quenched with saturated aqueous NH₄Cl (10 mL) andextracted with EtOAc (200 mL×3). The combined organic layers were driedover sodium sulfate, filtered and evaporated and purified by silica gelchromatography (eluting with 5:1 petroleum ether/ethyl acetate) to givethe product. MS (ESI) calcd. for (C₁₆H₁₃ClF₂NO₂) [M+H]⁺, 324.0, found,324.1. ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.14 (m, 1H), 7.03-6.85 (m, 3H),4.77-4.56 (m, 1H), 2.69-2.53 (m, 1H), 2.52-2.42 (m, 1H), 2.39 (s, 3H),2.26-2.13 (m, 1H), 2.00-1.85 (m, 1H).

Step 4:1-(7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)ethanol

A mixture of1-(7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)ethanone(130 mg, 0.40 mmol) and NaBH₄ (16 mg, 0.40 mmol) in MeOH (5 mL) wasstirred at 0° C. for 0.5 h. The reaction was poured into water (20 mL)and extracted with EtOAc (50 mL×3). The combined organic layers weredried over sodium sulfate, filtered and evaporated and the residue waspurified by silica gel chromatography (eluting with 5:1 petroleumether/ethyl acetate) to give the product. MS (ESI) calcd. for(C₁₆H₁₅ClF₂NO₂) [M+H]⁺, 326.0, found, 325.8. ¹H NMR (400 MHz, CDCl₃) δ7.25-7.16 (m, 1H), 7.04-6.90 (m, 2H), 6.85 (d, J=3.3 Hz, 1H), 4.25-4.01(m, 2H), 2.56-2.42 (m, 1H), 2.04 (s, 1H), 2.03-1.91 (m, 1H), 1.35-1.29(m, 3H).

Step 5: ethyl 5-(2,4-difluorophenyl)-2-(1-hydroxyethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of1-(7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)ethanol(130 mg, 0.4 mmol) in EtOH (20 mL) was added potassium acetate (117 mg,1.2 mmol) and PdCl₂(dppf) (29 mg, 0.05 mmol) under N₂ atmosphere. Themixture was degassed and backfilled with CO (three times). The resultingmixture was stirred under 50 psi CO at 70° C. for 12 h. The mixture wasconcentrated under reduced pressure to give the crude product, which waspurified by silica gel chromatography (ISCO®; 4 g SepaFlash® Column,eluting with 0% to 20% ethyl acetate/petroleum ether) to afford theproduct. MS (ESI) calcd. for (C₁₉H₂₀F₂NO₄) [M+H]⁺, 364.1, found, 364.1.¹H NMR (400 MHz, CD₃OD) δ 7.58 (s, 1H), 7.46-7.35 (m, 1H), 7.23-7.03 (m,2H), 4.44-4.34 (m, 2H), 4.20-4.05 (m, 1H), 4.02-3.87 (m, 1H), 2.79 (dtd,J=6.0, 11.9, 17.5 Hz, 1H), 2.66-2.53 (m, 1H), 2.22-2.02 (m, 1H),1.83-1.68 (m, 1H), 1.42-1.29 (m, 6H).

Step 6: ethyl(S)-2-((S)-1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate,ethyl(S)-2-((R)-1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate,ethyl(R)-2-((S)-1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(R)-2-((R)-1-(difluoromethoxy)ethyl)-5-(2A-difluorophenyl)-3-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of ethyl5-(2,4-difluorophenyl)-2-(1-hydroxyethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(85 mg, 0.23 mmol) and CuI (17 mg, 0.09 mmol) in CH₃CN (3 mL) was addeddropwise 2,2-difluoro-2-(fluorosulfonyl)acetic acid (200 mg, 1.13 mmol)at 45° C. under N₂ and the reaction was stirred for 2 h at 50° C. Thereaction was quenched with saturated aqueous NaHCO₃ (5 mL) and extractedwith EtOAc (20 mL×3). The combined organic layers were dried over sodiumsulfate, filtered and evaporated to give crude product, which waspurified by silica gel chromatography (eluting with 5:1 petroleumether/ethyl acetate) to give two diastereomers of the product. MS (ESI)calcd. for (C₂₀H₂₀F₄NO₄) [M+H]⁺, 414.1, found, 414.0. and MS (ESI)calcd. for (C₂₀H₂₀F₄NO₄) [M+H]⁺, 414.1, found, 414.0.

Each diastereomeric mixture of enantiomers was resolved by chiral SFC(Column: Chiralpak Whelk-01 250×30 mm, 10 um; Mobile phase: 45% to 45%EtOH (containing 0.05% DEA) in CO₂; Flow rate: 60 mL/min) to afford thefour isomers of the product.

Isomer 1: MS (ESI) calcd. for (C₂₀H₂₀F₄NO₄) [M+H]⁺, 414.1, found, 414.1.

Isomer 2: MS (ESI) calcd. for (C₂₀H₂₀F₄NO₄) [M+H]⁺, 414.1, found, 414.1.

Isomer 3: MS (ESI) calcd. for (C₂₀H₁₉F₄NO₄) [M+H]⁺, 414.1, found, 414.1.

Isomer 4: MS (ESI) calcd. for (C₂₀H₁₉F₄NO₄) [M+H]⁺, 414.1, found, 414.1.

Step 7:(S)-2-((S)-1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano2,3-bpyridine-7-carboxamide,(S)-2-((R)-1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide,(R)-2-((S)-1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-2-((R)-1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one isomer of ethyl2-(1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(10 mg, 0.023 mmol) other in ammonia (10 M in MeOH) (15 mL) was stirredat 25° C. for 12 h. The mixture was concentrated under reduced pressureto give one isomer of the title compound. MS (ESI) calcd. for(C₁₈H₁₇F₄N₂O₃) [M+H]⁺, 385.1, found, 385.1. ¹H NMR (400 MHz, CD₃OD) δ7.59 (s, 1H), 7.45-7.35 (m, 1H), 7.20-7.07 (m, 2H), 6.77-6.31 (m, 1H),4.54-4.43 (m, 1H), 4.34 (d, J=11.0 Hz, 1H), 2.82 (ddd, J=5.7, 12.2, 17.4Hz, 1H), 2.59 (dd, J=2.2, 17.4 Hz, 1H), 2.05 (td, J=2.6, 13.9 Hz, 1H),1.88-1.73 (m, 1H), 1.45 (d, J=6.4 Hz, 3H).

Similar treatment of the other isomers of ethyl2-(1-(difluoromethoxy)ethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other isomers of the title compound.

Isomer 2: MS (ESI) calcd. for (C₁₈H₁₇F₄N₂O₃) [M+H]⁺, 385.1, found,385.1. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (br. s., 1H), 7.44-7.33 (m, 1H),7.21-7.03 (m, 2H), 6.77-6.26 (m, 1H), 4.45 (d, J=5.5 Hz, 1H), 4.39-4.26(m, 1H), 2.90-2.72 (m, 1H), 2.67-2.49 (m, 1H), 2.04 (d, J=9.4 Hz, 1H),1.85-1.69 (m, 1H), 1.44 (d, J=6.3 Hz, 3H).

Isomer 3: MS (ESI) calcd. for (C₁₈H₁₇F₄N₂O₃) [M+H]⁺, 385.1, found,385.1. H NMR (400 MHz, CD₃OD) δ 7.58 (s, 1H), 7.46-7.31 (m, 1H), 7.12(q, J=7.7 Hz, 2H), 6.75-6.26 (m, 1H), 4.53-4.42 (m, 1H), 4.31 (d, J=11.0Hz, 1H), 2.79 (ddd, J=5.7, 12.1, 17.4 Hz, 1H), 2.67-2.51 (m, 1H), 2.14(dd, J=2.7, 11.0 Hz, 1H), 1.84-1.65 (m, 1H), 1.50-1.37 (m, 3H).

Isomer 4: MS (ESI) calcd. for (C₁₈H₁₇F₄N₂O₃) [M+H]⁺, 385.1, found,385.1. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (s, 1H), 7.45-7.32 (m, 1H),7.23-7.02 (m, 2H), 6.81-6.23 (m, 1H), 4.58-4.41 (m, 1H), 4.30 (d, J=10.6Hz, 1H), 2.79 (ddd, J=5.5, 12.0, 17.3 Hz, 1H), 2.66-2.52 (m, 1H),2.21-2.07 (m, 1H), 1.84-1.66 (m, 1H), 1.48-1.34 (m, 3H).

Compounds of Formula I (where, in Scheme 3, R^(2A), and R^(3A) are eachhydrogen and R², R³, ring B, n, and each R¹ are as described in formulaI or the alternative embodiments described herein) may be preparedaccording to Scheme 3 by various reactions on alcohol 3-1 (e.g.alkylation, fluorination, oxidation followed by fluorination, etc.)followed by treatment with ammonia.

Example 3-1A and 3-1B

3-1A:(R)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand 3-1B:(S)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: ethyl2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a mixture of ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(Intermediate 2-4, 94 mg, 0.27 mmol) and copper(I) iodide (10.3 mg, 0.05mmol) in MeCN (10 mL) was added 2,2-difluoro-2-(fluorosulfonyl)aceticacid (96 mg, 0.54 mmol) and the mixture was stirred at 45° C. for 2.5 hunder N₂ protection. The reaction was cooled to room temperature,basified to pH-8 with saturated aqueous NaHCO₃ and water (10 mL) andextracted with ethyl acetate (2×10 mL). The organic phases were driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe crude product, which was purified by Prep-TLC (silica gel, elutingwith 1:1 petroleum ether/ethyl acetate) to give the product. MS (ESI)calcd. for (C₁₉H₁₈F₄NO₄) [M+H]⁺, 400.2, found, 400.2. ¹H NMR (400 MHz,CD₃OD) δ 7.61 (s, 1H), 7.37-7.46 (m, 1H), 7.07-7.20 (m, 2H), 6.30-6.71(m, 1H), 4.51-4.61 (m, 1H), 4.39 (q, J=7.1 Hz, 2H), 4.08-4.20 (m, 2H),2.85 (ddd, J=5.8, 11.9, 17.4 Hz, 1H), 2.57-2.67 (m, 1H), 2.10 (td,J=2.8, 13.8 Hz, 1H), 1.75-1.88 (m, 1H), 1.38 (t, J=7.2 Hz, 3H).

Step 2: ethyl(S)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(R)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

Racemic ethyl2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(40 mg, 0.100 mmol) was resolved by chiral SFC (Column: Chiralpak AD250×30 mm, 5 um; Mobile phase: 30% to 30% IPA (containing 0.05% DEA) inCO₂; Flow rate: 70 mL/min) to give the two enantiomers.

Step 3:(S)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one enantiomer of ethyl2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(20 mg, 0.05 mmol) in ammonia (10 M in MeOH) (40 mL) was stirred at 20°C. for 16 h. The mixture was concentrated under reduced pressure. Theresidue was purified by Prep-HPLC (Column: Phenomenex Gemini C18250×21.2 mm, 5 um; Mobile phase: 30% to 60% water (containing 10 mMNH₄HCO₃)-ACN; Flow rate: 25 mL/min) to give one enantiomer of the titlecompound. MS (ESI) calcd. for (C₁₇H₁₅F₄N₂O₃) [M+H]⁺, 371.1, found,371.0. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (s, 1H), 7.34-7.42 (m, 1H),7.07-7.16 (m, 2H), 6.25-6.70 (m, 1H), 4.49-4.56 (m, 1H), 4.06-4.17 (m,2H), 2.82 (dd, J=5.67, 11.93, 17.22 Hz, 1H), 2.58 (d, J=16.04 Hz, 1H),2.03-2.11 (m, 1H), 1.72-1.85 (m, 1H)

Similar treatment of the other enantiomer of ethyl2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other enantiomer of the title compound. MS (ESI) calcd. for(C₁₇H₁₅F₄N₂O₃) [M+H]⁺, 371.1, found, 371.0. ¹H NMR (400 MHz, CD₃OD) δ7.58 (s, 1H), 7.33-7.42 (m, 1H), 7.07-7.17 (m, 2H), 6.27-6.71 (m, 1H),4.49-4.56 (m, 1H), 4.06-4.16 (m, 2H), 2.82 (dd, J=5.48, 11.84, 17.12 Hz,1H), 2.58 (d, J=16.43 Hz, 1H), 2.03-2.12 (m, 1H), 1.72-1.85 (m, 1H).

The following compounds were prepared according to the proceduresdescribed for Example 3-1A and 3-1B.

MS MS Ex- (ESI) (ESI) ample Structure Name calcd found ¹H NMR 3-2A

(S)- or (R)-2- ((difluoro- methoxy)methyl)- 5-(4- fluorophenyl)-3,4-dihydro-2H- pyrano[2,3- b]pyridine-7- carboxamide 353.1 352.9 (400MHz, CD₃OD) 7.61 (br. s., 1H), 7.35-7.50 (m, 2H), 7.11-7.30 (m, 2H),6.23-6.74 (m, 1H), 4.55 (br. s., 1H), 4.01-4.18 (m, 2H), 2.88-3.06 (m,1H), 2.70 (d, J = 16.54 Hz, 1H), 2.02- 2.15 (m, 1H), 1.64-1.84 (m, 1H).3-2B

(R)- or (S)-2- ((difluoro- methoxy)methyl)- 5-(4- fluorophenyl)-3,4-dihydro-2H- pyrano[2,3- b]pyridine-7- carboxamide 353.1 352.9 (400MHz, CD₃OD) 7.61 (br. s., 1H), 7.44 (br. s., 2H), 7.23 (t, J = 7.61 Hz,2H), 6.22-6.74 (m, 1H), 4.55 (br. s., 1H), 4.13 (br. s., 2H), 2.97 (d, J= 13.45 Hz, 1H), 2.70 (d, J = 16.54 Hz, 1H), 1.99-2.16 (m, 1H), 1.77(br. s., 1H) 3-3A

(S)- or (R)-2- ((difluoro- methoxy)methyl)- 5-(2- methylthiazol-5-yl)-3,4-dihydro- 2H-pyrano[2,3- b]pyridine-7- carboxamide 356.1 355.9(400 MHz, CD₃OD) 7.89 (br. s., 1H), 7.76 (br. s, 1H), 6.24-6.73 (m, 1H),4.53 (br. s., 1H), 4.14 (br. s., 2H), 2.76 (br. s., 3H), 2.17 (br. s.,1H), 1.29 (br. s., 1H) 3-3B

(R)- or (S)-2- ((difluoro- methoxy)methyl)- 5-(2- methylthiazol-5-yl)-3,4-dihydro- 2H-pyrano[2,3- b]pyridine-7- carboxamide 356.1 355.9(400 MHz, CD₃OD) 7.89 (s, 1H), 7.76 (s, 1H), 6.25- 6.73 (m, 1H), 4.55(br. s., 1H), 4.14 (d, J = 7.28 Hz, 2H), 2.90-3.15 (m, 2H), 2.77 (s,3H), 2.18 (d, J = 8.38 Hz, 1H), 1.74-1.91 (m, 1H) 3-4A

(S)- or (R)-2- ((difluoro- methoxy)methyl)- 5-(1- (difluoromethyl)-1H-pyrazol-4-yl)- 3,4-dihydro-2H- pyrano[2,3- b]pyridine-7- carboxamide374.1 375.0 (400 MHz, CD₃OD) 8.49 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H),7.39-7.76 (m, 1H), 6.28-6.72 (m, 1H), 4.48- 4.62 (m, 1H), 4.08-4.22 (m,2H), 2.90-3.18 (m, 2H), 2.19 (dd, J = 3.09, 11.03 Hz, 1H), 1.74-1.95 (m,1H). 3-4B

(R)- or (S)-2- ((difluoro- methoxy)methyl)- 5-(1- (difluoromethyl)-1H-pyrazol-4-yl)- 3,4-dihydro-2H- pyrano[2,3- b]pyridine-7- carboxamide374.1 375.0 (400 MHz, CD₃OD) 8.49 (s, 1H), 8.09 (s, 1H), 7.82 (s, 1H),7.39-7.75 (m, 1H), 6.29-6.72 (m, 1H), 4.48- 4.60 (m, 1H), 4.06-4.22 (m,2H), 2.87-3.18 (m, 2H), 2.12-2.29 (m, 1H), 1.77-1.92 (m, 1H).

Example 3-5A and 3-5B

(S)-5-(2,4-difluorophenyl)-2-(methoxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-(methoxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: ethyl5-(2,4-difluorophenyl)-2-(methoxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a stirred solution of ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(Intermediate 2-4, 150 mg, 0.43 mmol) and iodomethane (67.0 mg, 0.47mmol) in dry DMF (4 mL) was added sodium hydride (18.89 mg, 0.472 mmol)at 0° C. under N₂ atmosphere. The resulting mixture was stirred at 0° C.for 30 min. The solution was concentrated under reduced pressure, theresidue was purified by prep-TLC (silica gel, eluting with 2:1 ethylacetate/petroleum ether) to afford the product. MS (ESI) calcd. for(C₁₉H₂₀F₂NO₄) [M+H]⁺, 364.1, found, 364.0.

Step 2: ethyl(S)-5-(2,4-difluorophenyl)-2-(methoxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(R)-5-(2,4-difluorophenyl)-2-(methoxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

Racemic ethyl5-(2,4-difluorophenyl)-2-(methoxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(93 mg, 0.256 mmol) was separated by SFC (Column: Chiralpak OJ 250×30mm, 5 um; Mobile phase: 45% to 45% MeOH (containing 0.05% DEA) in CO₂;Flow rate: 60 mL/min) to afford the two enantiomers.

Step 3:(S)-5-(2,4-difluorophenyl)-2-(methoxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-(methoxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one enantiomer of ethyl5-(2,4-difluorophenyl)-2-(methoxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(41 mg, 0.11 mmol) in ammonia (10 M in MeOH) (15 mL) was stirred at 26°C. for 12 h. The mixture was concentrated under reduced pressure and theresidue was purified by prep-TLC (silica gel, eluting with 2:1 ethylacetate/petroleum ether) to afford one enantiomer of the title compound.MS (ESI) calcd. for (C₁₇H₁₇F₂N₂O₃) [M+H]⁺, [335.1], found, [335.0]. ¹HNMR (400 MHz, CDCl₃) δ 7.71 (s, 2H), 7.26-7.22 (m, 1H), 6.99-6.89 (m,2H), 5.50 (s, 1H), 4.46-4.44 (m, 1H), 3.73-3.62 (m, 2H), 3.44 (s, 3H),2.74-2.56 (m, 2H), 2.15-2.02 (m, 1H), 1.85-1.79 (m, 1H).

Similar treatment of the other enantiomer of ethyl5-(2,4-difluorophenyl)-2-(methoxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other enantiomer of the title compound. MS (ESI) calcd. for(C₁₇H₁₇F₂N₂O₃) [M+H]⁺, [335.1], found, [335.0]. ¹H NMR (400 MHz, CDCl₃)δ 7.66 (s, 2H), 7.21-7.15 (m, 1H), 6.94-6.84 (m, 2H), 5.50 (s, 1H),4.41-4.39 (m, 1H), 3.68-3.57 (m, 2H), 3.39 (s, 3H), 2.70-2.50 (m, 2H),2.10-1.97 (m, 1H), 1.80-1.74 (m, 1H).

Example 3-6A and 3-6B

(S)-5-(2,4-difluorophenyl)-2-(fluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-(fluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: ethyl5-(2,4-difluorophenyl)-2-(fluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(Intermediate 2-4, 300 mg, 0.86 mmol) in DCM (15 mL) at −40° C. wasadded DAST (0.34 ml, 2.6 mmol) in DCM (3 mL). The reaction mixture wasstirred at 0° C. for 100 min under N₂. The mixture was quenched withsaturated aqueous NaHCO₃ (30 mL) and extracted with DCM (2×20 mL). Thecombined organics were dried with Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (eluting with 20:1 to 1:3 petroleum ether/ethyl acetate)to afford the product. MS (ESI) calcd for (C₁₈H₁₇F₃NO₃) [M+H]⁺, 352.1,found, 352.1.

Step 2: ethyl(S)-5-(2,4-difluorophenyl)-2-(fluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(R)-5-(2,4-difluorophenyl)-2-(fluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

Racemic ethyl5-(2,4-difluorophenyl)-2-(fluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(990 mg, 2.82 mmol) was resolved by chiral SFC (Column: ChiralpakWhelk-01 250×30 mm, 10 um; Mobile phase: 50% to 50% EtOH (containing0.05% DEA) in CO₂; Flow rate: 60 mL/min) to give the two enantiomers.

Step 3:(S)-5-(2,4-difluoropheny)-2-(fluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-(fluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one enantiomer of ethyl5-(2,4-difluorophenyl)-2-(fluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(485 mg, 1.38 mmol) in ammonia (10 M in MeOH) (50 mL) was stirred at 23°C. for 4 h. The mixture was concentrated in vacuo to furnish. The solidwas washed with CH₃CN (2 mL). The mixture was filtered and the solidresidue was dried under reduced pressure to afford one enantiomer of thetitle compound. MS (ESI) calcd. for (C₁₆H₁₄F₃N₂O₂) [M+H]⁺, 323.0, found,323.1. ¹H NMR (400 MHz, CD₃OD) δ 7.59 (s, 1H), 7.43-7.37 (m, 1H),7.16-7.10 (m, 2H), 4.87-4.54 (m, 3H), 2.87-2.80 (m, 1H), 2.63-2.58 (m,1H), 2.09-2.06 (m, 1H), 1.84-1.79 (m, 1H).

Similar treatment of the other enantiomer of ethyl5-(2,4-difluorophenyl)-2-(fluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylatefurnished the other enantiomer of the title compound. MS (ESI) calcd.for (C₁₆H₁₄F₃N₂O₂) [M+H]⁺, 323.0, found, 323.1. ¹H NMR (400 MHz, CD₃OD)δ 7.59 (s, 1H), 7.43-7.37 (m, 1H), 7.16-7.10 (m, 2H), 4.87-4.54 (m, 3H),2.86-2.81 (m, 1H), 2.63-2.59 (m, 1H), 2.09-2.04 (m, 1H), 1.82-1.79 (m,1H).

Example 3-7A and 3-7B

3-7A:(R)-2-(difluoromethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand 3-7B:(S)-2-(difluoromethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: ethyl5-(2,4-difluorophenyl)-2-formyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(Intermediate 3-1)

A stirred solution of racemic ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(Intermediate 2-4, 300 mg, 0.86 mmol) in DCM (20 mL) was added DMP (474mg, 1.1 mmol) at 0° C. under N₂ atmosphere. The resulting mixture wasstirred at 0° C. for 1 h. Saturated aqueous NaHCO₃ (50 mL) was added.The organic layer was separated, dried over anhydrous NaSO₄, filteredand concentrated under reduced pressure to afford the product which wasused in the next step without further purification. MS (ESI) calcd. for(C₁₈H₁₈F₂NO₅) [M+H+H₂O]⁺, 366.1, found, 366.1.

Step 2: ethyl2-(difluoromethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of ethyl5-(2,4-difluorophenyl)-2-formyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(380 mg, 1.1 mmol) in DCM (20 mL) and EtOH (0.01 mL) was added DAST(0.289 ml, 2.2 mmol) at 0° C. After addition, the mixture was stirred at24° C. for 2 h. To the reaction mixture was slowly added saturatedaqueous sodium bicarbonate (20 mL). The organic layer was separated,dried over sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by prep-TLC (silica gel, eluting with 1:2 ethylacetate/petroleum ether) to give the product. MS (ESI) calcd. for(C₁₈H₁₆F₄NO₃) [M+H]⁺, 370.2, found, 370.0.

Step 3:2-(difluoromethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of ethyl2-(difluoromethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]-pyridine-7-carboxylate(81 mg, 0.22 mmol) in ammonia (10 M in MeOH) (15 mL) was stirred at 25°C. for 3 h. The mixture was concentrated under reduced pressure to givethe product. MS (ESI) calcd. for (C₁₆H₁₃F₄N₂O₂) [M+H]⁺, [341.1], found,[341.0].

Step 4:(R)-2-(difluoromethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(S)-2-(difluoromethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

Racemic ethyl2-(difluoromethyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide(64 mg, 0.19 mmol) was separated by SFC (Column: Chiralpak AD 250×30 mm,5 um; Mobile phase: 20% to 20% MeOH (containing 0.05% DEA) in CO₂; Flowrate: 60 mL/min) to afford the two enantiomers:

One enantiomer: MS (ESI) calcd. for (C₁₆H₁₃F₄N₂O₂) [M+H]⁺, 341.1, found,341.0. ¹H NMR (400 MHz, CD₃OD) δ 7.63 (s, 1H), 7.43-7.38 (m, 1H),7.17-7.11 (m, 2H), 6.22-5.94 (m, 1H), 4.87-4.54 (m, 1H), 3.30-2.81 (m,1H), 2.67-2.63 (m, 1H), 2.19-2.16 (m, 1H), 1.90-1.84 (m, 1H).

Other enantiomer: MS (ESI) calcd. for (C₁₆H₁₃F₄N₂O₂) [M+H]⁺, 341.1,found, 341.0. ¹H NMR (400 MHz, CD₃OD) δ 7.63 (s, 1H), 7.43-7.38 (m, 1H),7.17-7.11 (m, 2H), 6.22-5.94 (m, 1H), 4.62-4.54 (m, 1H), 3.30-2.81 (m,1H), 2.67-2.63 (m, 1H), 2.19-2.16 (m, 1H), 1.90-1.84 (m, 1H).

Example 3-8A and 3-8B

(S)-5-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: ethyl5-(2,4-difluorophenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand5-(2,4-difluorophenyl)-2-(2,2,2-trifluoro-1-((trimethylsilyl)oxy)ethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of ethyl5-(2,4-difluorophenyl)-2-formyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(Intermediate 3-1, 700 mg, 2.0 mmol), cesium fluoride (918 mg, 6.1 mmol)in THF (15 mL) was added trimethyl(trifluoromethyl)silane (860 mg, 6.1mmol) at 0° C. under N₂. The reaction mixture was stirred at 0° C. for 2h under N₂. The mixture was quenched with H₂O (15 mL), and extractedwith EtOAc (3×25 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. Silica gel chromatography eluting with 20:1 to 2:1petroleum ether:ethyl acetate afforded the products. MS (ESI) calcd. for(C₂₂H₂₅F₅NO₄Si) [M+H]⁺, 490.5, found, 490.4. ¹H NMR (400 MHz, CDCl₃) δ7.48 (s, 1H), 6.97-7.07 (m, 1H), 6.72-6.88 (m, 2H), 4.21-4.38 (m, 3H),2.59 (br. s., 1H), 2.47 (br. s., 1H), 1.83-2.04 (m, 1H), 1.62-1.83 (m,1H), 1.23 (t, J=7.04 Hz, 3H), 0.01 (d, J=11.35 Hz, 9H).

Step 2: ethyl5-(2,4-difluorophenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of ethyl5-(2,4-difluorophenyl)-2-(2,2,2-trifluoro-1-((trimethylsilyl)oxy)ethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(300 mg, 0.61 mmol) in ethanol (15 mL) was added K₂CO₃ (102 mg, 0.74mmol) at 18° C. The mixture was stirred at 18° C. for 40 min. Themixture was filtered and the filtrate was concentrated in vacuo and theresidue was purified by prep-TLC (silica gel, eluting with 2:1 petroleumether:ethyl acetate) to give the product. MS (ESI) calcd. for(C₁₉H₁₇F₅NO₄) [M+H]⁺, 418.0, found, 417.9. ¹H NMR (400 MHz, CDCl₃) δ7.68 (d, J=10.17 Hz, 1H), 7.22 (br. s., 1H), 6.86-7.06 (m, 2H),4.53-4.66 (m, 1H), 4.43 (quin, J=7.24 Hz, 2H), 4.11 (q, J=7.30 Hz, 1H),2.81 (br. s., 1H), 2.58-2.69 (m, 1H), 2.04-2.19 (m, 2H), 1.40 (q, J=7.43Hz, 3H).

Step 3:5-(2,4-difluorophenyl)-2-(2,2,2-trifluoro-1-(((methylthio)carbonothioyl)oxy)ethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylicacid

To a solution of ethyl5-(2,4-difluorophenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(280 mg, 0.67 mmol) in THF (2 mL) was added NaH (40.3 mg, 1.0 mmol) at0° C. under N₂. After stirring for 30 min, carbon disulfide (0.10 mL,1.68 mmol) and iodomethane (0.31 mL, 5.00 mmol) were added and themixture was stirred at 0° C. under N₂ for 1 h. The reaction was dilutedwith 15 mL water and 5 drops HCl (concentrated, 12M), extracted withEtOAc (3×15 mL), the combined organics were dried over Na₂SO₄, filteredand concentrated in vacuo to give the product, which was used in nextstep without further purification. MS (ESI) calcd. for (C₁₉H₁₅F₅NO₄S₂)[M+H]⁺, 480.1, found, 480.2.

Step 4: ethyl5-(2,4-difluorophenyl)-2-(2,2,2-trifluoro-1-(((methylthio)carbonothioyl)oxy)ethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of5-(2,4-difluorophenyl)-2-(2,2,2-trifluoro-1-(((methylthio)carbonothioyl)oxy)ethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylicacid (430 mg, 0.90 mmol) in dry EtOH (10 mL) was added sulfurousdichloride (320 mg, 2.69 mmol) under N₂. The mixture was stirred at 85°C. under N₂ for 2.5 h. The mixture was quenched with H₂O (15 mL), thenthe mixture was adjusted to pH=8 with solid NaHCO₃. The mixture wasextracted with EtOAc (3×20 mL). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Silica gel chromatography eluting with 10:1 to 5:1 petroleum ether:ethylacetate afforded the product. MS (ESI) calcd for (C₂₁H₁₉F₅NO₄S₂) [M+H]⁺,508.4, found, 508.3. ¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J=2.74 Hz, 1H),7.17-7.23 (m, 1H), 6.87-7.04 (m, 2H), 4.68-4.82 (m, 1H), 4.42 (dq,J=2.35, 7.04 Hz, 2H), 2.70-2.89 (m, 1H), 2.66 (br. s., 1H), 2.60 (s,3H), 2.07-2.25 (m, 1H), 1.80-2.00 (m, 1H), 1.39 (dt, J=1.96, 7.04 Hz,3H).

Step 5: ethyl5-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of ethyl5-(2,4-difluorophenyl)-2-(2,2,2-trifluoro-1-(((methylthio)carbonothioyl)oxy)ethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(230 mg, 0.45 mmol) and tributylstannane (1.18 g, 4.05 mmol) in Toluene(10 mL) was added azobisisobutyronitrile (20 mg, 0.12 mmol) under N₂.The reaction mixture was heated to 100° C. and stirred under N₂ for 1 h.The reaction was diluted with 20 mL water, extracted with EtOAc (20mL×3), the combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product. Theresidue was purified by silica gel chromatography (eluting with 10:1 to5:1 petroleum ether:ethyl acetate) to give the product. MS (ESI) calcdfor (C₁₉H₁₇F₅NO₃) [M+H]⁺, 402.1, found, 402.1. ¹H NMR (400 MHz, CDCl₃) δ7.65 (s, 1H), 7.18-7.24 (m, 1H), 6.87-7.04 (m, 2H), 4.58 (td, J=5.23,10.27 Hz, 1H), 4.42 (q, J=7.04 Hz, 2H), 2.71-2.94 (m, 2H), 2.42-2.65 (m,2H), 2.12-2.24 (m, 1H), 1.69-1.86 (m, 1H), 1.39 (t, J=7.04 Hz, 3H).

Step 6: ethyl(S)-5-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(R)-5-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

Racemic ethyl5-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(120 mg, 0.3 mmol) was resolved via chiral SFC (Column: Chiralpak IC250×30 mm, 10 um; Mobile phase: 30% to 30% IPA (containing 0.05% DEA inCO₂; Flow rate: 6 mL/min) to give the two enantiomers which were used innext step without further purification.

Step 7:(S)-5-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one enantiomer of ethyl5-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(45 mg, 0.11 mmol) in ammonia (10 M in MeOH) (20 mL) was stirred at 10°C. for 20 h. The mixture was concentrated and purified by Prep-HPLC(Column: Phenomenex Synergi C18 150×30 mm, 4 um; Mobile phase: 43% to63% water (containing 0.05% HCl)-ACN; Flow rate: 25 mL/min) to give oneenantiomer of the title compound. MS (ESI) calcd. for (C₁₇H₁₄F₅N₂O₂)[M+H]⁺, 373.1, found, 372.9. ¹H NMR (400 MHz, CD₃OD) δ 7.59 (br. s.,1H), 7.38 (d, J=6.26 Hz, 1H), 7.01-7.18 (m, 2H), 4.65 (br. s., 1H),2.49-2.89 (m, 4H), 2.05-2.24 (m, 1H), 1.79 (br. s., 1H).

Similar treatment of the other enantiomer of ethyl5-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other enantiomer of the title compound. MS (ESI) calcd. for(C₁₇H₁₄F₅N₂O₂) [M+H]⁺, 373.1, found, 372.9. ¹H NMR (400 MHz, CD₃OD) δ7.60 (s, 1H), 7.35-7.45 (m, 1H), 7.08-7.18 (m, 2H), 4.67 (br. s., 1H),2.54-2.90 (m, 4H), 2.09-2.20 (m, 1H), 1.73-1.88 (m, 1H)

Example 3-9A, 3-9B, 3-9C and 3-9D

(2S,3R)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide,(2S,3S)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide,(2R,3R)-2-((difluoromethoxy)methyl)-5-(2,4-difluoropheny)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(2R,3S)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: ethyl (2S,3R)-, (2S,3S)-, (2R,3R) or(2R,3S)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a solution of one isomer of ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(Intermediate 2-5A, 2-5B, 2-5C or 2-5D) 140 mg, 0.39 mmol) inacetonitrile (8 mL) was added copper(I) iodide (14.7 mg, 0.077 mmol) andthe mixture was heated to 45° C. under N₂.2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.2 mL, 1.9 mmol) was addeddropwise, the mixture was stirred at 45° C. for 2 h. The mixture wascooled in an ice bath and saturated aqueous NaHCO₃ (15 mL) was added.The aqueous layer was extracted with EtOAc (25 mL×3). The combinedorganic layers were washed with brine (sat. 20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudeproduct. The residue was purified by Prep-TLC (silica gel, eluting with2:1 petroleum ether:ethyl acetate) to give one isomer of the product. MS(ESI) calcd. for (C₂₀H₂₀F₄NO₄) [M+H]⁺, 414.1, found, 414.3. ¹H NMR (400MHz, CDCl₃) δ 7.59 (d, J=6.26 Hz, 1H), 7.13-7.19 (m, 1H), 6.85-7.01 (m,2H), 5.99-6.48 (m, 1H), 4.37 (q, J=7.04 Hz, 2H), 3.93-4.26 (m, 3H),2.01-2.61 (m, 3H), 1.24-1.41 (m, 3H), 0.77-1.06 (m, 3H).

Similar treatment of the other isomers of ethyl5-(2,4-difluorophenyl)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other isomers of the product.

Step 2: (2S,3R)-, (2S,3S)-, (2R,3R) or(2R,3S)-2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one isomer of ethyl2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(13 mg, 0.03 mmol) in ammonia (10 M in MeOH) (10 mL) was stirred at roomtemperature for 10 h. The mixture was concentrated and the residue waspurified by Prep-HPLC (Column: Phenomenex Synergi C18 150×30 mm, 4 um;Mobile phase: 40% to 60% water (containing 0.1% TFA)-ACN; Flow rate: 25mL/min) to give one isomer of the title compound. MS (ESI) calcd. for(C₁₈H₁₇F₄N₂O₃) [M+H]⁺, 385.1, found, 385.0. ¹H NMR (400 MHz, CD₃OD) δ7.59 (s, 1H), 7.28-7.45 (m, 1H), 6.99-7.21 (m, 2H), 6.23-6.71 (m, 1H),4.58 (br. s., 1H), 4.01-4.19 (m, 2H), 2.88-3.03 (m, 1H), 2.23-2.44 (m,2H), 0.90 (d, J=6.26 Hz, 3H).

Similar treatment of the other isomers of ethyl2-((difluoromethoxy)methyl)-5-(2,4-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other isomers of the title compound.

Isomer 2: MS (ESI) calcd. for (C₁₈H₁₇F₄N₂O₃) [M+H]⁺, 385.1, found,385.0. ¹H NMR (400 MHz, CD₃OD) δ 7.59 (br. s., 1H), 7.29-7.44 (m, 1H),7.04-7.19 (m, 2H), 6.24-6.73 (m, 1H), 4.59 (br. s., 1H), 4.10 (br. s.,2H), 2.97 (br. s., 1H), 2.32 (br. s., 2H), 0.90 (d, J=5.87 Hz, 3H).

Isomer 3: MS (ESI) calcd. for (C₁₈H₁₇F₄N₂O₃) [M+H]⁺, 385.1, found,385.0. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (br. s., 1H), 7.38 (d, J=5.09 Hz,1H), 7.12 (d, J=7.43 Hz, 2H), 6.22-6.71 (m, 1H), 4.07-4.32 (m, 3H),2.40-2.69 (m, 2H), 2.06 (br. s., 1H), 1.04 (d, J=4.30 Hz, 3H).

Isomer 4: MS (ESI) calcd. for (C₁₈H₁₇F₄N₂O₃) [M+H]⁺, 385.1, found,385.0. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (s, 1H), 7.29-7.46 (m, 1H),7.04-7.20 (m, 2H), 6.25-6.68 (m, 1H), 4.10-4.31 (m, 3H), 2.41-2.69 (m,2H), 2.07 (br. s., 1H), 1.05 (d, J=6.65 Hz, 3H).

Compounds of Formula I (where, in Scheme 4, R is —(C₁₋₄)haloalkyl, R′ isH or methyl, ring B, n, and each R¹ are as described in Formula I or thealternative embodiments described herein) may be prepared according toScheme 4 via cyclization of 4-1 to generate the acid 4-2. This isfollowed by amide formation and reduction to the amine. Subsequentalkylation (or protection for secondary amines) followed bycarbonylation and treatment with ammonia affords the tertiary amines (afinal deprotection furnished secondary amines).

Example 4-1A and 4-1B

(S)-5-(2,4-difluorophenyl)-2-((methyl(2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-((methyl(2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1:7-chloro-5-(2,4-difluorophenyl)-N-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxamide

To a solution of7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxylicacid (Intermediate 3-2, 0.8 g, 2.5 mmol) and HATU (1.2 g, 3.7 mmol) inDMF (10 mL). The mixture was stirred at 25° C. for 10 min under N₂. ThenDIPEA (0.68 g, 4.9 mmol) was added followed by slow addition of2,2,2-trifluoroethanamine (0.37 g, 3.7 mmol). The mixture was stirred at25° C. for 2 h. The mixture was poured into H₂O (100 mL) and extractedwith EtOAc (30 mL×3). The combined organic layers were purified bysilica gel chromatography [ISCO®: 4 g SepaFlash column eluting with 0%to 20% ethyl acetate/petroleum ether] to give the product. MS (ESI)calcd for (C₁₇H₁₃CF₅N₂O₂) [M+H]⁺, 407.0 found, 407.0.

Step 2:N-((7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)-2,2,2-trifluoroethanamine

To a solution of7-chloro-5-(2,4-difluorophenyl)-N-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-2-carboxamide(0.45 g, 1.1 mmol) and BH₃.S(CH₃)₂ (44 mmol) in THF (10 mL). The mixturewas stirred at 0° C. for 10 min then at 45° C. for another 2 h. Themixture was quenched with CH₃OH (40 mL) and concentrated under reducepressure. The residue was purified by silica gel chromatography [ISCO®:4 g SepaFlash column eluting with 0% to 20% ethyl acetate/petroleumether] to give the product. MS (ESI) calcd for (C₁₇H₁₅ClF₅N₂O) [M+H]⁺,392.9 found, 392.9.

Step 3:N-((7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)-2,2,2-trifluoro-N-methylethanamine

A solution ofN-((7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)-2,2,2-trifluoroethanamine(0.1 g, 0.26 mmol) and CH₂O (0.016 g, 0.51 mmol) in DCE (10 mL) wasstirred at 25° C. NaBH(OAc)₃ (0.11 g, 0.51 mmol) was added to thesolution followed by a drop of AcOH. The mixture was stirred at 25° C.for 8 h. The mixture was poured into H₂O (20 mL), the pH was adjusted to˜9 with the addition of NaHCO₃, and the mixture was extracted with EtOAc(20 mL×3). The combined organic extracts were dried over anhydrousNa₂SO₄, filtered and concentrated. the residue was purified by silicagel chromatography [ISCO®: 4 g SepaFlash column eluting with 0% to 20%ethyl acetate/petroleum ether] to give the product. MS (ESI) calcd for(C₁₆H₁₉ClF₅N₂O) [M+H]⁺, 407.0 found, 407.0.

Step 4: ethyl5-(2,4-difluorophenyl)-2-((methyl(2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a stirred solution ofN-((7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)-2,2,2-trifluoro-N-methylethanamine(0.13 g, 0.32 mmol) in EtOH (20 mL) was added Pd(dppf)Cl₂ (0.023 g,0.032 mmol) and KOAc (0.064 g, 0.64 mmol). The mixture was heated to 60°C. and stirred for 18 h under 50 psi CO. The mixture was concentratedunder reduce pressure and the resulting solution was diluted with water(20 mL) and extracted with ethyl acetate (20 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by Prep-TLC (silica gel, eluting with 4:1 petroleumether/ethyl acetate) to afford the product. MS (ESI) calcd for(C₂₁H₂₂F₅N₂O₃) [M+H]⁺, 445.1, found, 445.0. ¹H NMR (400 MHz, CDCl₃) δ7.56 (s, 1H), 7.24-7.11 (m, 1H), 6.99-6.79 (m, 2H), 4.36 (q, J=7.0 Hz,2H), 4.28 (td, J=4.9, 9.8 Hz, 1H), 3.10 (q, J=9.0 Hz, 2H), 3.04-2.91 (m,1H), 2.78 (dd, J=6.7, 13.3 Hz, 1H), 2.49 (s, 3H), 2.16-2.02 (m, 1H),1.74-1.56 (m, 1H), 1.33 (t, J=7.2 Hz, 3H)

Step 5: ethyl(S)-5-(2,4-difluorophenyl)-2-((methyl(2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateand ethyl(R)-5-(2,4-difluorophenyl)-2-((methyl(2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

Racemicethyl-5-(2,4-difluorophenyl)-2-((methyl(2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(100 mg, 0.28 mmol) was resolved by chiral SFC (Column: Chiralpak AD250×30 mm, 5 um; Mobile phase: 20% to 20% IPA (containing 0.05% DEA) inCO₂; Flow rate: 60 mL/min) to afford the two enantiomers. MS (ESI) calcdfor (C₂₁H₂₂F₅N₂O₃) [M+H]⁺, 445.1, found, 445.0. MS (ESI) calcd for(C₂₁H₂₂F₅N₂O₃) [M+H]⁺, 445.1, found, 445.0.

Step 6(S)-5-(2,4-difluorophenyl)-2-((methyl(2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-((methyl(2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

A solution of one enantiomer of ethyl5-(2,4-difluorophenyl)-2-((methyl(2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(40 mg, 0.09 mmol) in ammonia (10 M in MeOH) (40 mL) was stirred at 20°C. for 16 h. The mixture was concentrated under reduced pressure. Theresidue was purified by Prep-TLC to afford one enantiomer of the titlecompound. MS (ESI) calcd for (C₁₉H₁₉F₅N₃O₂) [M+H]⁺, 416.1, found, 416.3.

Similar treatment of the other enantiomer of ethyl5-(2,4-difluorophenyl)-2-((methyl(2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylateafforded the other enantiomer of the title compound. MS (ESI) calcd for(C₁₉H₁₉F₅N₃O₂) [M+H]⁺, 416.1, found, 416.3.

Example 4-2A and 4-2B

(S)-5-(2,4-difluoropheny)-2-(((2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-(((2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideStep 1: tert-butyl((7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamate

To a stirred solution ofN-((7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)-2,2,2-trifluoroethanamine(150 mg, 0.38 mmol) in DCM (10 mL) was added di-tert-butyl dicarbonate(194 mg, 3.3 mmol), Et₃N (820 mg, 3.8 mmol) andN,N-dimethylpyridin-4-amine (4.7 mg, 0.04 mmol). Then the mixture wasstirred at 25° C. for 16 h. The solution was concentrated under reducedpressure. The residue was purified by silica gel chromatography (elutingwith 1:0 to 20:1 petroleum ether/ethyl acetate) to afford the product.MS (ESI) calcd. for (C₂₂H₂₃ClF₅N₂O₃) [M+H]⁺, 493.12, found, 493.

Step 2: ethyl2-(((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate

To a stirred solution ofN-((7-chloro-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)-2,2,2-trifluoroethanamine(71 mg, 0.14 mmol) in EtOH (15 mL) was added Pd(dppf)Cl₂ (10.6 mg, 0.014mmol) and KOAc (28 mg, 0.29 mmol). Then the solution was heated to 60°C. and stirred for 18 h under 50 psi CO. The solution was concentratedunder reduced pressure. The resulting solution was diluted with water(20 mL) and extracted with EtOAc (20 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by Prep-TLC (silica gel, eluting with3:1 petroleum ether:ethyl acetate) to afford the product. MS (ESI)calcd. for (C₂₅H₂₈F₅N₂O₅) [M+H]⁺, 531.18, found, 531.3.

Step 3: tert-butyl((7-carbamoyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamate

Ethyl2-(((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)methyl)-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxylate(53 mg, 0.1 mmol) in NH₃/MeOH (10 M, 15 mL) was stirred at 25° C. for 16h. The mixture was concentrated under reduced pressure to give theproduct which was used in subsequent steps without further purification.MS (ESI) calcd. for (C₂₃H₂₅F₅N₃O₄) [M+H]⁺, 502.17, found, 502.2.

Step 4: tert-butyl(S)-((7-carbamoyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamateand tert-butyl(R)-((7-carbamoyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamate

Tert-butyl((7-carbamoyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamate(40 mg, 0.08 mmol) was separated by SFC (Column: Chiralpak AS 250×30 mm,5 um; Mobile phase: 10% to 10% MeOH (containing 0.05% DEA) in CO₂; Flowrate: 60 mL/min) to afford the two enantiomers.

Step 4:(S)-5-(2,4-difluorophenyl)-2-(((2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamideand(R)-5-(2,4-difluorophenyl)-2-(((2,2,2-trifluoroethyl)amino)methyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide

One enantiomer of tert-butyl((7-carbamoyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamate(20 mg, 0.04 mmol) was stirred in DCM (3 mL) and TFA (0.5 mL) at 25° C.for 1 h. The reaction mixture was concentrated under reduced pressure toafford one enantiomer of the title compound. MS (ESI) calcd for(C₁₈H₁₇F₅N₃O₂) [M+H]⁺, 402.1, found, 402.1.

Similar treatment of the other enantiomer of tert-butyl((7-carbamoyl-5-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamateafforded the other enantiomer of the title compound. MS (ESI) calcd for(C₁₈H₁₇F₅N₃O₂) [M+H]⁺, 402.1, found, 402.1.

Example 5A and 5B

(5S,8R)-4-(2,4-difluorophenyl)-5,6,7,8-tetrahydro-5,8-epoxyquinoline-2-carboxamideand(5R,8S)-4-(2,4-difluorophenyl)-5,6,7,8-tetrahydro-5,8-epoxyquinoline-2-carboxamideStep 1: 3-(trimethylsilyl)pyridin-2-ol

To a solution of diisopropylamine (31.0 mL, 218 mmol) in THF (200 mL)was added n-butyllithium (95 mL, 238 mmol) at −78° C. After stirring for1 h, a solution of pyridin-2-ol (9 g, 95 mmol) in THF (100 mL) was addedat −78° C. The mixture was gradually warmed to 0° C. over 1 h.Chlorotrimethylsilane (13.20 mL, 104 mmol) was added to the mixture at0° C. The resulting mixture was gradually warmed to 25° C. over 14 h.The reaction was quenched with H₂O (300 mL) and extracted with EtOAc(3×100 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel chromatography (ISCO®; 40 g SepaFlash® Column,eluting with 0-30% ethyl acetate/petroleum ether) to give the product.MS (ESI) calcd. for (C₈H₁₄NOSi) [M+H]⁺, 168.1, found, 168.0. ¹H NMR (400MHz, CDCl₃) δ 12.07 (br. s., 1H), 7.54 (dd, J=1.8, 6.5 Hz, 1H), 7.33(dd, J=2.0, 6.3 Hz, 1H), 6.23 (t, J=6.5 Hz, 1H), 0.28 (s, 9H).

Step 2: 3-(trimethylsilyl)pyridin-2-yl trifluoromethanesulfonate

To a solution of 3-(trimethylsilyl)pyridin-2-ol (13 g, 78 mmol) inpyridine (100 mL) was added trifluoromethanesulfonic anhydride (16 mL,95 mmol) at 0° C. under N₂ over 20 min. The mixture was gradually warmedto 25° C. and stirred for another 14 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography (ISCO®; 120 g SepaFlash® Column, eluting with0-10% ethyl acetate/petroleum ether) to give the product. MS (ESI)calcd. for (C₉H₁₃F₃NO₃SSi) [M+H]⁺, 300.0, found, 300.0. ¹H NMR (400 MHz,CDCl₃) δ 8.33 (dd, J=2.0, 4.7 Hz, 1H), 7.92 (dd, J=1.6, 7.0 Hz, 1H),7.31 (dd, J=5.1, 7.0 Hz, 1H), 0.38 (s, 9H).

Step 3: 5,8-dihydro-5,8-epoxyquinoline

To a solution of furan (1.21 mL, 16.74 mmol) and cesium fluoride (1.015g, 6.68 mmol) in acetonitrile (10 mL) was added3-(trimethylsilyl)pyridin-2-yl trifluoromethanesulfonate (1 g, 3.34mmol) in acetonitrile (10 mL) slowly at 0° C. The mixture was stirred at28° C. for 15 h. The mixture was concentrated. Water (20 mL) was addedand the mixture was extracted with ethyl acetate (3×20 mL). The combinedorganic layers were washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography (ISCO®; 12 g SepaFlash® Column, eluting with 0 to 40%methyltetrabutylether/petroleum ether) to give the product. ¹H NMR (400MHz, CDCl₃) δ 8.03 (d, J=5.1 Hz, 1H), 7.42 (d, J=7.0 Hz, 1H), 7.19-7.07(m, 2H), 6.90-6.79 (m, 1H), 5.78 (s, 1H), 5.61 (s, 1H).

Step 4: 5,6,7,8-tetrahydro-5,8-epoxyquinoline

To a solution of 5,8-dihydro-5,8-epoxyquinoline (500 mg, 3.44 mmol) inEtOH (14 mL) was added hydrazine hydrate (0.683 mL, 13.78 mmol) under 10Psi O₂ atmosphere. The mixture was stirred at 30° C. for 15 h. Themixture was concentrated. The residue was purified by silica gelchromatography (ISCO®; 12 g SepaFlash® Column, eluting with 0 to 30%ethyl acetate/petroleum ether) to give the product. ¹H NMR (400 MHz,CDCl₃) δ 8.32-8.23 (m, 1H), 7.49 (d, J=6.8 Hz, 1H), 7.05 (dd, J=5.1, 7.4Hz, 1H), 5.50-5.34 (m, 2H), 2.17-2.08 (m, 2H), 1.56-1.37 (m, 2H).

Step 5: 5,6,7,8-tetrahydro-5,8-epoxyquinoline 1-oxide

To a solution of 5,6,7,8-tetrahydro-5,8-epoxyquinoline (200 mg, 1.359mmol) in DCM (2 mL) was added m-CPBA (630 mg, 3.10 mmol). The mixturewas stirred at 25° C. for 15 h. The mixture was quenched with saturatedaqueous Na₂SO₃ and extracted with DCM (3×10 mL). The combined organiclayers were washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by silica gelchromatography (ISCO®; 20 g SepaFlash® Column, eluting with 0% to 5%DCM/MeOH) to give the product. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J=5.7Hz, 1H), 7.18-7.04 (m, 2H), 5.85 (br. s., 1H), 5.50 (br. s., 1H), 2.19(d, J=7.9 Hz, 2H), 1.67 (t, J=8.7 Hz, 1H), 1.51-1.40 (m, 1H).

Step 6: 4-chloro-5,6,7,8-tetrahydro-5,8-epoxyquinoline

To a mixture of 5,6,7,8-tetrahydro-5,8-epoxyquinoline 1-oxide (230 mg,1.410 mmol) and lithium chloride (72 mg, 1.698 mmol) in acetonitrile (6mL) was added phosphoryl trichloride (1.08 g, 7.04 mmol) at 25° C. Theresulting mixture was stirred at 100° C. for 2 h. After cooling to roomtemperature, the reaction mixture was poured into 50 g of ice andbasified with solid NaHCO₃ to pH ˜8. The mixture was extracted withEtOAC (3×20 mL). The combined organic layers were washed with brine (10mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by Prep-TLC (silica gel,eluting with 4:1 ethyl acetate/petroleum ether) to give the product. MS(ESI) calcd. for (C₉H₉ClNO) [M+H]⁺, 182.0, found, 181.8. ¹H NMR (400MHz, CDCl₃) δ 8.15 (d, J=5.5 Hz, 1H), 7.02 (d, J=5.5 Hz, 1H), 5.56 (d,J=3.5 Hz, 1H), 5.38 (d, J=3.9 Hz, 1H), 2.14 (dd, J=2.7, 9.8 Hz, 2H),1.47 (d, J=9.0 Hz, 2H).

Step 7: 4-chloro-5,6,7,8-tetrahydro-5,8-epoxyquinoline 1-oxide

A mixture of 4-chloro-5,6,7,8-tetrahydro-5,8-epoxyquinoline (150 mg,0.826 mmol) and mCPBA (335 mg, 1.652 mmol) in DCM (5 mL) was stirred at40° C. for 14 h. The reaction mixture was quenched with saturatedaqueous Na₂SO₃ (20 mL) and extracted with DCM (3×15 mL). The combinedorganic phases were washed with brine (10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by Prep-TLC (silica gel, eluting with 10:1 DCM/MeOH) togive the product. MS (ESI) calcd. for (C₉H₉ClNO₂) [M+H]⁺, 198.0, found,197.8. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J=6.8 Hz, 1H), 7.05 (d, J=6.8Hz, 1H), 5.83 (d, J=3.5 Hz, 1H), 5.57 (d, J=3.5 Hz, 1H), 2.28-2.14 (m,2H), 1.66 (t, J=8.7 Hz, 1H), 1.57-1.43 (m, 1H).

Step 8: 4-chloro-5,6,7,8-tetrahydro-5,8-epoxyquinoline-2-carbonitrile

To a mixture of 4-chloro-5,6,7,8-tetrahydro-5,8-epoxyquinoline 1-oxide(44 mg, 0.223 mmol) and trimethylsilanecarbonitrile (66 mg, 0.665 mmol)in CHCl₃ (2 mL) was added dimethylcarbamic chloride (72 mg, 0.670 mmol)at 25° C. The resulting mixture was stirred at 60° C. for 14 h. Themixture was concentrated and purified by Prep-TLC (silica gel, elutingwith 4:1 petroleum ether/ethyl acetate) to give the product. MS (ESI)calcd. for (C₁₀H₈ClN₂O) [M+H]⁺, 207.0, found, 206.8. ¹H NMR (400 MHz,CDCl₃) δ 7.42 (s, 1H), 5.55 (d, J=4.3 Hz, 1H), 5.38 (d, J=3.9 Hz, 1H),2.16 (dd, J=3.1, 10.6 Hz, 2H), 1.53-1.36 (m, 2H).

Step 9:4-(2,4-difluorophenyl)-5,6,7,8-tetrahydro-5,8-epoxyquinoline-2-carbonitrile

A mixture of4-chloro-5,6,7,8-tetrahydro-5,8-epoxyquinoline-2-carbonitrile (80 mg,0.387 mmol), (2,4-difluorophenyl)boronic acid (183 mg, 1.162 mmol),K₃PO₄ (250 mg, 1.178 mmol), and PdCl₂(dtbpf) (40 mg, 0.061 mmol) in THF(4 mL) was degassed and backfilled with N₂ (three times). The mixturewas heated to 85° C. for 2.5 h. After cooling to room temperature, thereaction mixture was diluted with water (10 mL) and extracted with EtOAc(3×10 mL). The combined organic phases were washed with brine (5 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by Prep-TLC (silica gel, eluting with1:4 ethyl acetate/petroleum ether) to give the product. MS (ESI) calcd.for (C₁₆H₁₁F₂N₂O) [M+H]⁺, 285.1, found, 284.9. ¹H NMR (400 MHz, CDCl₃) δ7.53 (s, 1H), 7.39-7.29 (m, 1H), 7.12-6.96 (m, 2H), 5.47-5.37 (m, 2H),2.23 (d, J=8.2 Hz, 2H), 1.63 (d, J=11.7 Hz, 2H).

Step 10:(5S,8R)-4-(2,4-difluorophenyl)-5,6,7,8-tetrahydro-5,8-epoxyquinoline-2-carbonitrileand(5R,8S)-4-(2,4-difluorophenyl)-5,6,7,8-tetrahydro-5,8-epoxyquinoline-2-carbonitrile

Racemic4-(2,4-difluorophenyl)-5,6,7,8-tetrahydro-5,8-epoxyquinoline-2-carbonitrile(90 mg, 0.317 mmol) was resolved by chiral SFC (Column: Chiralpak AD250×30 mm, 5 um; Mobile phase: 20% to 100% EtOH (containing 0.05% DEA)in CO₂; Flow rate: 65 mL/min) to give the two enantiomers.

Step 11:(5S,8R)-4-(2,4-difluorophenyl)-5,6,78-tetrahydro-5,8-epoxyquinoline-2-carboxamideand(5R,8S)-4-(2,4-difluorophenyl)-5,6,7,8-tetrahydro-5,8-epoxyquinoline-2-carboxamide

To a solution of one enantiomer of4-(2,4-difluorophenyl)-5,6,7,8-tetrahydro-5,8-epoxyquinoline-2-carbonitrile(40 mg, 0.141 mmol) in DMSO (2 mL) was added hydrogen peroxide (65 mg,0.573 mmol) and K₂CO₃ (10 mg, 0.072 mmol) at 25° C. The resultingmixture was stirred at 25° C. for 2 h. The reaction was quenched withsaturated aqueous Na₂SO₃ (0.2 mL) and the mixture was directly purifiedby Prep-HPLC (Column: Waters Xbridge Prep OBD C18 150×30 mm, 5 um;Mobile phase: 24% to 54% water (containing 0.05% ammonia hydroxidev/v)-ACN; Flow rate: 25 mL/min) to give one enantiomer of the titlecompound. MS (ESI) calcd. for (C₁₆H₁₃F₂N₂O₂) [M+H]⁺, 303.1, found,303.1. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.79 (br. s., 1H),7.50-7.37 (m, 1H), 7.13-6.93 (m, 2H), 5.63 (br. s., 1H), 5.42 (br. s.,2H), 2.31-2.20 (m, 2H), 1.66 (d, J=7.0 Hz, 2H).

Similar treatment of the other enantiomer of4-(2,4-difluorophenyl)-5,6,7,8-tetrahydro-5,8-epoxyquinoline-2-carbonitrileafforded the other enantiomer of the title compound. MS (ESI) calcd. for(C₁₆H₁₃F₂N₂O₂) [M+H]⁺, 303.1, found, 303.1. ¹H NMR (400 MHz, CDCl₃) δ8.08 (s, 1H), 7.79 (br. s., 1H), 7.51-7.37 (m, 1H), 7.15-6.93 (m, 2H),5.61 (br. s., 1H), 5.41 (d, J=3.9 Hz, 2H), 2.30-2.19 (m, 3H), 1.66 (d,J=7.0 Hz, 2H).

Biological Assays

The utility of the compounds of the invention as an inhibitor ofmetabotropic glutamate receptor activity, in particular mGluR2 activity,may be demonstrated by methodology known in the art and as described asfollows. Inhibition constants (IC₅₀s; the concentration of compoundrequired to provide 50% of maximal activity) are determined as follows.The compounds of the invention were tested in a fluorescence laserimaging plate reader based assay. This assay is a common functionalassay to monitor Ca²⁺ mobilization in whole cells expressing recombinantreceptor coupled with a promiscuous G-protein. CHO (Chinese hamsterovary) dhfr− cells stably expressing recombinant human mGluR2 and Gα16loaded with Fluo-4 AM (Invitrogen, Carlsbad Calif., USA) were treatedwith various concentrations of each of the tested compounds of theinvention and the Ca²⁺ response was monitored on a FLIPR384 instrument(Molecular Devices, Sunnydale Calif., USA). Maximal agonist activity wasmeasured in the presence of 2,500 nM glutamate and the inhibitionprovided by a range of compound concentrations sufficient to minimallyand maximally inhibit the glutamate-dependent response was monitoredover time. The maximum calcium response at each concentration ofcompound for agonist or antagonist were plotted as dose responses andthe curves were fitted with a four parameter logistic equation givingIC₅₀ and Hill coefficient using the iterative non-linear curve fittingsoftware ADA (Merck & Co., Inc.). Data in the following table lists theactivity of each compound to inhibit glutamate-dependent mGluR2 activityin this cellular assay.

Example IC50 value (nM) 1-1 277 1-2A 376 1-2B 21 1-3A 65 1-3B 121-4A >3000 1-4B 1765 1-5A >3000 1-5B 326 1-6A >3000 1-6B 1801 1-7A >30001-7B 172 2-1A 38 2-1B 179 2-2A 195 2-2B 15 2-2C 35 2-2D 81 2-3A 20 2-3B32 2-4A 20 2-4B 69 2-5 6 2-6A 10 2-6B 26 2-7 25 2-8A 8 2-8B 14 2-9A 182-9B 114 2-9C 11 2-9D 57 3-1A 7 3-1B 19 3-2A 18 3-2B 86 3-3A 536 3-3B2519 3-4A 274 3-4B 1491 3-5A 26 3-5B 27 3-6A 52 3-6B 10 3-7A 18 3-7B 903-8A 12 3-8B 24 3-9A 7 3-9B 19 3-9C 15 3-9D 9 4-1A 25 4-1B 74 4-2A 214-2B 28 5-1A 159 5-1B 500

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims that follow and that such claims be interpreted as broadly asis reasonable.

What is claimed is:
 1. A compound having the structure:


2. A compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt.
 3. A compound having the structure:


4. A compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt.
 5. A compound having the structure:


6. A compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt.
 7. A compound having the structure:


8. A compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt.
 9. A compound having the structure:


10. A compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt.
 11. A compound having the structure:


12. A compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt.
 13. A compound having the structure:


14. A compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt.
 15. A pharmaceutical composition comprising a therapeuticallyeffective amount of the compound of claim 1 and a pharmaceuticallyacceptable carrier.
 16. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of the compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt, according to claim
 2. 17. A pharmaceutical composition comprisinga therapeutically effective amount of the compound of claim 3 and apharmaceutically acceptable carrier.
 18. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of the compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt, according to claim
 4. 19. A pharmaceutical composition comprisinga therapeutically effective amount of the compound of claim 5 and apharmaceutically acceptable carrier.
 20. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of the compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt, according to claim
 6. 21. A pharmaceutical composition comprisinga therapeutically effective amount of the compound of claim 7 and apharmaceutically acceptable carrier.
 22. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of the compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt, according to claim
 8. 23. A pharmaceutical composition comprisinga therapeutically effective amount of the compound of claim 9 and apharmaceutically acceptable carrier.
 24. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of the compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt, according to claim
 10. 25. A pharmaceutical composition comprisinga therapeutically effective amount of the compound of claim 11 and apharmaceutically acceptable carrier.
 26. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of the compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt, according to claim
 12. 27. A pharmaceutical composition comprisinga therapeutically effective amount of the compound of claim 13 and apharmaceutically acceptable carrier.
 28. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of the compound having the structure:

wherein said compound is in the form of a pharmaceutically acceptablesalt, according to claim 14.